Bicyclolactam compounds, use thereof and intermediates for preparing thereof

ABSTRACT

A bicyclolactam compound of the formula (1) is disclosed, which has an excellent anxiolytic effect, is high in safety, and is useful as an effective component of medicinals which are greatly diminished in side effects such as hypnotic, muscle relaxant and sedative effects ##STR1## A bicyclolactam derivative represented by the following formula (1) is also disclosed, and is useful as an effective component of an anxiolytic agent ##STR2##

This is a divisional of application Ser. No. 08/908,601 filed on Aug. 8,1997 now U.S. Pat. No. 6,004,975, which is a continuation-in-part ofapplication Ser. No. 08/537,854, filed Nov. 15, 1995, abandoned, whichis a national stage application of PCT/JP95/003 filed Mar. 29, 1995, andSer. No. 08/776,654, filed Feb. 7, 1997, abandoned, which is a nationalstage application of PCT/JP96/01565, filed on Jun. 7, 1996.

TECHNICAL FIELD

The present invention relates to anxiolytic agents comprising abicyclolactam derivative as their effective component and to thetreatment of anxiety.

BACKGROUND ART

With rapid diversification of the social environment in recent years, anincreasing number of people are suffering from anxiety, and it has beenexpected to develop psychosomatic therapies and excellent therapeuticagents.

Benzodiazepine compounds such as diazepam have found wide use ofanxiolytics. This group of agents, however, generally have side effectssuch as hypnotic effect, muscle relaxant effect and sedative effect.Serotonin anxiolytic agents such as buspirone are also recentlydeveloped as anxiolytics which are different from the benzodiazepinecompounds in activity mechanism. Reportedly these serotonin agents aregenerally lesser than the benzodiazepines in side effects such ashypnotic, muscle relaxant and sedative effects, but they are lower inanxiolytic effect and have the problems of diminishing voluntarymovements presumably owing to their activity as a dopamine antagonist,and causing serotonin syndrome which appears attributable to theirproperties as a full agonist for serotonin 1A receptor.

On the other hand, the bicyclolactam derivatives of the presentinvention are known compounds disclosed in International PublicDisclosure No. WO 91/11434, and are known to have a cerebral functionimproving effect, cerebral metabolism activating or anoxic brain damageprotecting effect and effect against senile dementia. Nevertheless,nothing whatsover is known about the anxiolytic effect of thesecompounds.

Anxiety is an essential symptom of neuroses and is a neurotic disorderinvolving no organic disorder of the brain.

In contrast, the term dementia refers to an organic mental disorderwhich is the sustained deterioration of acquired intelligence due to anorganic disorder of the brain. Many of dementias are caused by a widevariety of organic disorders of the brain and involve generaldeterioration of mental functions such as memory, calculation,orientation and discretion, leading to failure of correct recognition,judgement or behavior as to one's own situation.

"Diagnostic and Statistical Manual of Mental Disorders," Revised 3rd Ed.(DSM-III-R), widely used as a diagnostic manual and published byAmerican Psychiatric Association in 1987, clearly classifies thesediseases in the chapters "Anxiety Disorders (or Anxiety and PhobicNeuroses)" and "Organic Mental Syndromes and Organic Mental Disorders"(see "DSM-IIII-R Classification of Mental Disorders and DiagnosticManual," (2nd Ed.), translated by Saburo Takehasi et al., published byTgaku Shoin (1988), pp. 71˜94 and 121˜129).

An object of the present invention is to provide a novel anxiolyticagent comprising a bicyclolactam derivative as its effective component,and a therapy of anxiety.

DISCLOSURE OF THE INVENTION

We have investigated the pharmacological activation of bicyclolactamderivatives from various viewpoints, consequently found that thosecompounds have a very high anxiolytic effect and are yet greatlydiminished in side effects such as hynoptic, muscle relaxant andsedative effects and accomplished the present invention. Morespecifically, the invention provides an anxiolytic agent comprising asits effective component a bicyclolactam derivatives represented by thefollowing formula ##STR3## wherein R¹ is a hydrogen atom or hydroxylgroup, R² is benzoyl group which may optionally have at least onesubstituent, l is 1 or 2, m is 0 or 1 and n is 0, 1 or 2, provided thecase where both of m and n represent 0 simultaneously is excluded.

The present invention further includes a method of treating anxietycomprising administering an effective amount of the compound (1) tomammals including man, and also use of the compound (1) for thepreparation of medicinals for treating anxiety.

Existing as bicyclolactam derivatives of the formula (1) arestereoisomers due to the presence of the bicycle ring, and alsogeometric isomers and optical isomers due to the presence of the carbonatom at the bridgehead position of the bicycle ring and the carbon atomhaving R¹ attached thereto. The present invention includes all of theseisomers.

In view of the numbers l, m and n, the following ten kinds of bicycloring skeletons can be present in the compounds of the formula (1). Theinvention includes all of these cases. ##STR4##

Preferable among these is the case wherein the skeleton is (a), (b),(f), (g) or (h). More preferable is the case wherein m is 0, i.e., (a),(b), (f) or (g). The most preferable is (b), (f) or (g).

According to the invention, examples of substituents which may bepresent in the benzoyl group represented by R² are a halogen atom, loweralkyl group, lower alkoxyl group, nitro group, cyano group, hydroxylgroup or amino group. Examples of halogen atoms are fluorine, chloride,bromide and iodine atom, among which chloride atom is preferable.Examples of useful lower alkyl groups are straight-chain or branchedalkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyland hexyl group. Preferable among these are methyl and ethyl groups.Methyl group is more preferable. Examples of useful lower alkoxyl groupsare straight-chain or branched alkoxyl groups having 1 to 6 carbonatoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxygroup, among which methoxy and ethoxy groups are preferable. Methoxygroup is more preferable.

Preferable as R² of the compound represented by the formula (1) is abenzoyl group having as a substituent a halogen atom, lower alkyl group,lower alkoxyl group, nitro group, cyano group or amino group, morepreferably a benzoyl group having lower alkoxyl group. Especiallypreferable is a benzoyl group having methoxy group. The number ofsubstituents is preferably 1 to 3. The substituent may be present at anyof the ortho-, meta- and para-positions on the phenyl ring of thebenzoyl group.

Among the compounds of the formula (1), preferable are those wherein mis 0, and more preferable are those wherein R² is a benzoyl having loweralkoxyl group and wherein l is 1, m is 0 and n is 2, or 1 or 2, m is 0and n is 1, or l is 2, m is 0 and n is 2. More preferable are thosewherein R² is a benzoyl group having methoxy group and wherein l is 1, mis 0 and n is 2, or l is 2, m is 0 and n is 1, or l is 2, m is 0 and nis 2. In the case where R¹ is hydroxyl group, especially preferredcompounds are those wherein l is 1, m is 0 and n is 2.

Examples of the compound of the above formula (1) are

2-(4-methoxybenzoyl)-2-azabicyclo[3,3,0]octane-3-one,

2-(4-methoxybenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(p-toluyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(3,4-dichlorobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(3,5-dimethoxylbenzoyl)-3-azabicyclo[3, 4, 0]nonane-3-one,

2-(4-cyanobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(4-nitrobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(4-aminobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(4-chlorobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

8-(4-methoxybenzoyl)-8-azabicyclo[4, 3, 0]nonane-7-one,

2-(4-hydroxybenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

3-(4-methoxybenzoyl)-3-azabicyclo[3, 3, 0]octane-4-one,

3-(4-methoxybenzoyl)-3-azabicyclo[4, 3, 0]nonane-4-one,

3-(4-methoxybenzoyl)-3-azabicyclo[5, 3, 0]decane-4-one,

3-(4-methoxybenzoyl)-3-azabicyclo[4, 4, 0]decane-4-one,

3-(4-methoxybenzoyl)-3-azabicyclo[5, 4, 0]undecane-4-one,

7-(4-methoxybenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(p-toluyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(3,4-dichlorobenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(3,5-dimethoxybenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(4-cyanobenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(4-nitrobenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(4-aminobenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(4-aminobenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(4-chlorobenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-(4-hydroxybenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

2-(4-methoxybenzoyl)-2-azabicyclo[4, 3, 0]decane-3-one,

2-(p-toluyl)-2-azabicyclo[4, 4, 0]decane-3-one,

2-(3,4-dichlorobenzoyl)-2-azabicyclo[4, 3, 0]decane-3-one,

2-(3,5-dimethoxybenzoyl)-2-azabicyclo[4, 4, 0]decane-3-one,

2-(4-cyanobenzoyl)-2-azabicyclo[4, 3, 0]decane-3-one,

2-(4-nitrobenzoyl)-2-azabicyclo[4, 4, 0]decane-3-one,

2-(4-aminobenzoyl)-2-azabicyclo[4, 4, 0]decane-3-one,

2-(4-chlorobenzoyl)-2-azabicyclo[4, 4, 0]decane-3-one,

2-(4-hydroxybenzoyl)-2-azabicyclo[4, 4, 0]decane-3-one,

7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-hydroxy-7-(4-methoxybenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one, and

7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4, 4, 0]nonane-3-one.

Preferable examples are:

2-(4-methoxybenzoyl)-2-azabicyclo[4, 4, 0]decane-3-one,

2-(4-methoxybenzoyl)-2-azabicyclo[3, 3, 0]decane-3-one,

2-(4-methoxybenzoyl)-2-azabicyclo[4, 3, 0]decane-3-one,

2-(p-toluyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(3,4-dichlorobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(3,5-dimethoxybenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(4-cianobenzoyl)-2-azabicyclo[4, 3, 0]nonane-5-one,

2-(4-nitrobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(4-aminobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(4-chlorobenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

7-(4-methoxybenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

8-(4-methoxybenzoyl)-8-azabicyclo[4, 3, 0]nonane-7-one and

7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

More preferable examples are

2-(4-methoxybenzoyl)-2-azabicyclo[4, 4, 0]decane-3-one,

2-(4-methoxybenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one,

2-(4-methoxybenzoyl)-7-azabicyclo[4, 3, 0]nonane-8-one,

7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4, 3, 0]nonane-3-one

The bicyclolactam derivative of the formula (1) is a known compoundwhich is disclosed for example in International Public Disclosure No. WO91/11434 (U.S. Pat. No. 5,185,344, U.S. Pat. No. 5,214,039), etc.

The bicyclolactam derivative (1-a) of the present invention wherein R¹is hydrogen atom can be prepared, for example, by the following reactionprocess ##STR5## wherein R², e, m and n are as defined above, X ishalogen atom.

Bicyclolactam compound (2) is a known compound and is easily prepared bymethods disclosed in Journal of American Chemical Society, 77, 409(1955), Yakugaku Zasshi, 84, 674 (1964) and Journal of Chemical SocietyPerkin Transactions 1 11, 2563 (1982). The compound of the formula (1-a)can be prepared by reacting the bicyclolactam compound (2) with thehalide compound (3), in the presence of a base in an appropriatesolvent.

The solvent is not limited specifically insofar as it does notparticipate in the reaction. Examples of solvents generally useful arehydrocarbon halides such as dichlorolmethane and chloroform, esters suchas ethyl ether and tetrahydrofuran, aromatic hydrocarbons such asbenzene and toluene, aprotic polar solvents such as N,N-dimethylformamide and dimethylsulfoxide.

As to the proportion of the compound (2) and the halide compound (3), itis usual to use 0.5 to 2 moles. preferably one mole of the compound (3)per mole of the compound (2). Examples of bases are organic amines suchas triethylamine, pyridine and 4-dimethylaminopyridine, and inorganicbases such as sodium hydride and sodium amide. The amount of the base isusually 0.5 to 7 moles, preferably one mole per mole of the compound(2). The reaction temperature is 0 to 150° C., preferably 50 to 100° C.The reaction time is 1 to 48 hours, preferably 2 to 12 hours.

The bicyclolactam derivative (1-b) of the present invention wherein R¹is hydroxyl group can be prepared, for example, by the followingreaction process ##STR6## wherein R³ is hydrogen atom, halogen atom,lower alkyl group, lower alkoxyl group, nitro group, cyano group,hydroxyl group or amino group.

(i) A known compound A disclosed in J. Org. Chem., 42, 3764˜3767 (1977)is reacted with ethylene glycol in a suitable solvent in the presence ofan acid catalyst to obtain a compound B. The solvent to be used is notparticularly limited insofar as it does not participate in the reaction;it is, for example, an aromatic hydrocarbon such as benzene, toluene orxylene. Examples of useful acid catalysts are sulfuric acid,p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonicacid the like. The reaction is conducted using ethylene glycol and theacid catalyst each in an amount of about 1 to about 2 moles per mole ofthe compound A. The reaction temperature is 60° C. to a temperaturearound the boiling point of the solvent. For the completion of thereaction, the reaction line is 1 to 8 hours, preferable about 4 to about7 hours. The compound B obtained by the reaction can be used for thesubsequent reaction, as isolated or without being isolated.

(ii) Next, the compound B is reacted with a reducing agent in a suitablesolvent to obtain a compound C. The solvent to be used is not limitedspecifically insofar as it does not participate in the reaction.Examples of such solvents are methanol, ethanol, propanol, isopropanoland like alcohols, dioxane, 1,2-dimethoxyethane, tetrahydrofuran andlike ethers. Examples of useful reducing agents are lithium aluminumhydride, diisobutyl aluminum hydride, diborane, sodium boron hydride andthe like. The reaction is conducted using the reducing agent in about 1to about 1.5 moles per mole of the compound C. The reaction temperatureis 31 5° C. to room temperature, preferably about 0 to about 10° C. Thereaction time is preferably about 1 to about 3 hours. The compound Cresulting from the reaction can be used for the subsequent reaction, asisolated or without being isolated.

(iii) The compound C is reacted with p-nitrobenzoic acid,triphenylphosphine and diethyl azodicarboxylate in a suitable solvent toobtain a compound D. The solvent to be used is not limited specificallyinsofar as it does not participate in the reaction. Examples of suchsolvents are dioxane. 1,2-dimethoxyethane, tetrahydrofuran and likeethers, chloroform, dichloromethane, dichloroethane and like hydrocarbonhalides. The reaction is conducted using the latter three reactants eachin about 1 to about 3 moles per mole of the compound C. The reactiontemperature is -5 to 50° C., preferably about 0° C. to around roomtemperature. The reaction times is 1 to 15 hours, preferably about 6 toabout 12 hours. The compound D resulting from the reaction can be usedfor the subsequent reaction, as isolated or without being isolated.

(iv) The compound D is hydrolyzed in a suitable solvent with use of ananion exchange resin to obtain a compound E. The solvent to be used isnot limited specifically insofar as it will not participate in thereaction. Examples of such solvents are methanol, ethanol, propanol,isopropanol and like alcohols. The reaction is conducted using the anionexchange resin in about 1 to about 10 moles per mole of the compound D.The reaction temperature is room temperature to 100° C., and thereaction time is about 10 to about 24 hours. The compound E resultingfrom the reaction can be used for the subsequent reaction, as isolatedor without being isolated.

(v) The compound E is reacted with benzyl bromide in a suitable solventin the presence of a base to obtain a compopund F. The solvent to beused is not limited specifically insofar as it does not participate inthe reaction. Examples of such solvents are N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile and like aprotic polar solvents,dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers. Examplesof useful bases are trimethylamine, triethylamine, pyridine and liketertiary amines, potassium carbonate, sodium carbonate and like alkalimetal carbonate, and potassium hydride, sodium hydride and like alkalimetal hydrides. For the reaction, the base and benzyl bromide are usedeach in about 1 to about 2 moles per mole of the compound E. Thereaction temperature is room temperature to 100° C., preferably roomtemperature to about 70° C. The reaction time is 8 to 30 hours,preferably about 20 to about 28 hours. The compound F resulting from thereaction can be used for the subsequent reaction, as isolated or withoutbeing isolated.

(vi) The compound F is subjected to a ketal removing reaction in asuitable solvent with use of an acid to obtain a compound C. The solventis not limited specifically insofar as it does not participate in thereaction. Examples of solvents are alcohols such as methanol, ethanol,propanol and isopropanol, and ethers such as dioxane,1,2-dimethoxyethane and tetrahydrofuran. Examples of useful acids areacetic acid, trifluoroacetic acid, oxalic acid and like organic acids,hydrochloric acid, bromic acid, sulfuric acid, nitric acid and likeinorganic acids. The reaction temperature is 0 to 60° C., preferablyabout 10 to about 70° C. The reaction time is about 2 to about 8 hours.The compound C resulting from the reaction can be used for thesubsequent reaction, as isolated or without being isolated.

(vii - a) The compound G is reacted with hydroxylamine and sodiumacetate in a suitable solvent to obtain an oxime of the compound G. Thesolvent is not limited specifically insofar as it does not participatein the reaction. Examples of useful solvents are methanol, ethanol,propanol, isopropanol and like alcohols, dioxane, 1,2-dimethoxyethane,tetrahydrofuran and like ethers. Hydroxylamine and sodium acetate areused each in about 1.5 to 2 moles per mole of the compoudn G. Thereaction temperature is 0 to 50° C., preferably room temperature. Thereaction time is preferably 5 to 8 hours.

Subsequently, the resulting oxime of the compound G is reacted withp-toluenesulfonyl chloride in a suitable solvent in the presence of abase to obtain a p-tosylic acid ester of the compound G. Silica gel isadded to the ester in the same solvent, followed by a Beckmannrearrangement reaction to obtain a mixture of compound Ha and compoundHb. The solvent to be used is not limited specifically insofar as itdoes not participate in the reaction. Examples of such solvents arebenzene, toluene, xylene and like aromatic hydrocarbons, chloroform,dichloromethane, dichloroethane and like hydrocarbon halides. Examplesof useful bases are trimethylamine, triethylamine, pyridine and liketertiary amines. For the reaction, the base and p-tosyl chloride areused each in 2 to 3 moles per mole of the oxime of the compound G. Thereaction temperature for tosylation is about 0 to 10° C., and thereaction time is about 4 to about 8 hours. The Beckmann rearrangementreaction in silica gel is conducted at a temperature of about 10 toabout 10° C. for about 12 to about 24 hours.

(vii - b) The resulting mixture is reacted with a compound I in asuitable solvent in the presence of a base to obtain a compound Ja andcompound Jb. The solvent is not limited specifically insofar as it doesnot participate in the reaction. Examples of useful solvents arechloroform, dichloromethane, dichloroethane and like hydrocarbonhalides. Examples of useful bases are tertiary amines such astrimethylamine, triethylamine and pyridine. For the reaction, the baseis used in about 1 to about 2 moles per mole of the mixture. Thereaction temperature is about 5 to about 50° C., preferably about 10° C.to around room temperature. The reaction time is 12 to 36 hours,preferably about 24 to about 36 hours. The compound Ja or compound Jbresulting from the reaction can be used for the subsequent reaction, asisolated or without being isolated.

(viii) The compound Ja is hydrogenated in a suitable solvent in thepresence of palladium-carbon to obtain a compound (1-b). The solvent isnot limited specifically insofar as it does not participate in thereaction. Examples of useful solvents are methanol, ethanol, propanol,isopropanol and like alcohols, dioxane, 1,2-dimethoxyethane,tetrahydrofuran and like ethers, and methyl acetate, ethyl acetate andlike acetic acid esters. For the reaction, palladium-carbon is usedpreferably in the ratio of 0.5 to 1 by weight based on the compound Ja.The reaction temperature is preferably around room temperature to about50° C. The reaction time is about 10 to about 20 hours.

The compound (1) thus obtained can be isolated and purified by a usualmethod such as recrystallization or column chromatography. The racemiccompound obtained can be divided into the desired optical isomers, forexample, by fractional recrystallization for the separation of saltsfrom optically active acids or by passing a column packed with anoptically active carrier. The stereoisomers can be individuallyseparated off and purified by a usual method such as fractionalcrystallization or chromatography.

The anxiolytic agent embodying the present invention can be given orallyor parenterally to mammals including man. The pharmaceuticalpreparations of the present invention are not limited specifically inthe unit form of administration but can be in various forms inconformity with preventive or therapeutic purposes. These forms ofpreparations include, for example, oral preparations, injections,suppositories, external preparations (such as poultices and likeplasters, ointments, creams and lotions), eye drops, nasal drops orsprays, etc.

The anxiolytic agent of the present invention is prepared and used inthe form of a composition having a desired conventional pharmaceuticalcarrier or excipient incorporated therein by a usual method.

Stated more specifically, examples of carriers for use in formulatingthe agent as tablets, encapsulated preparations, granules, powders, etc.for oral administration are excipients such as lactose, sucrose, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose and silicic acid, binders such as water, ethanol, propanol,syrup, glucose solution, starch solution, gelatin solution,carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch,shellac, methyl cellulose, ethyl cellulose, potassium phosphate andpolyvinylpyrrolidone, disintegrators such as dried starch, sodiumalginate, agar powder, laminaria powder, sodium hydrogencarbonate,calcium carbonate, polyoyxethylene sorbitan fatty acid esters, sodiumlaurylsulfate, stearic acid monoglyceride, starch and lactose,disintegration suppresuants such as sucrose, stearic acid, cacao butterand hydrogenated oils, absorption promoters such as quaternary ammoniumbases and sodium laurylsulfate, humectants such as glycerin and starch,absorbents such as starch, lactose, kaolin, bentonite and colloidalsilinic acid, glazing agents such as purified talc, stearic acid salts,boric acid powder and polyethylene glycol, corrigents such as sucrose,bitter orange peel, citric acid and tartaric acid, etc. When required,the tablets can be those having a usual coating, such as sugar-coatedtablets, gelatin-coated tablets, enteric-coated tablets, film-coatedtablets, double-layer tablets and multi-layer tablets. The encapsulatedpreparation is made by mixing the present compound with carriers such asthose exemplified above and filling the mixture into hard gelatincapsules or soft capsules.

Liquid preparations for oral administration include aqueous or oilysuspensions, solutions, syrups and elixirs, and are prepared in theusual manner by adding a corrigent, buffer, stabilizer, flavoring agent,to the present compound. In this case, examples of useful corrigents arethose exemplified above, useful buffers include sodium citrate, anduseful stabilisers include tragacanth, gum arabic and gelatin, etc.

Injections are aqueous or oily suspensions and solutions, or powderyfillers and freeze-dried preparations which are dissolved when to beused. Injections are prepared in the usual manner by adding to thepresent compound a pH adjusting agent, buffer, stabilizer, isotonicagent, diluent, focal anesthetic, etc. Examples of pH adjusting agentsand buffers for use in this case are sodium citrate, sodium acetate,sodium phosphate and the like. Examples of useful stabilizers are sodiumpyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc. Examples ofuseful diluents are water, aqueous solution of lactic acid, ethylalcohol, propylene glycol, ethoxylated isostearyl alcohol,polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid ester,etc. Examples of useful focal anesthetics are procaine hydrochloride,lidocaine hydrochloride, etc.

In preparing suppositories, use can be made of carriers such aspolyethylene glycol, lanolin, cacao fat, esters of higher alcohols,gelatin, semisynthetic glyceride, etc., and when required, surfactantssuch as Tween (trademark).

Ointments (pastes, creams, gels, etc.) are prepared by admixing with thepresent compound a base, stabilizer, lubricant, preservative, etc. whichare usually used. Examples of bases are fluid paraffin, white petroleum,bleached beeswax, octyldodecyl alcohol, paraffin and the like. Examplesof useful preservatives are methyl p-hydroxybenzoate, ethylp-hydroxybenzoate, hydroxybenzoate, propyl p-hydroxybenzoate and thelike.

Plasters are prepared by applying the ointment, cream, gel, paste or thelike to a usual support in the conventional manner. Examples of suitablesupports are woven or nonwoven fabrics of cotton, staple fiber orchemical fiber, films of flexible polyvinyl chloride, polyethylene,polyurethane or the like, and foamed sheets of such material.

When required, the foregoing preparations may have further incorporatedtherein a coloring agent, preservative, perfume, flavoring, sweetenerand the like, and other medicinals.

The method of administering the pharmaceutical preparation of theinvention is not limited specifically but determined according to theform of preparation, age, sex and other conditions of the patient anddegree of symptom of the patient. For example, tablets, pellets,powders, solutions, suspensions, emulsions, granules and capsules aregiven orally. Suppositories are introduced into the rectum. Injectionsare intravenously given singly or as mixed with a usual auxiliarysolution such as glucose or amino acid solution. Further when required,they are singly administered intra-arterially, intramuscularly,intracutaneously, subcutaneously or intraperitoneally. Ointments areapplied to the skin, mucous membrane of the oral cavity, etc. Plastersare applied to the skin.

The dosage of the effective component of the preparation of theinvention can be suitably determined according to the mode ofadministration, age, sex and other conditions of the patient and degreeof the symptom. Generally the effective component is administered at adaily dose usually of 0.001 to 10 mg/kg body weight, preferably 0.01 to5 mg/kg body weight. The present preparation can be given once or inabout 2 to about four divided doses per day.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention will be described below with reference toreference examples, examples and test examples. However, the inventionis not limited by these examples.

Reference Example 1

In 100 ml of dichloromethane were dissolved 3.0 g (19.6 mmol) of2-azabicyclo[4, 4, 0]decane-3-one [Journal of American Chemical Society,77, 409 (1955)]. 3.35 g (19.5 mmol) of p-methoxybenzoyl chloride and2.38 g (23.5 mmol) of triethylamine and the solution was heated underreflux for 2 hours. After cooled, an organic layer was washed withwater, 10.0% hydrochloric acid and saturated aqueous solution of sodiumchloride, and dried over anhydrous magnesium sulfate. After removing thesolvent, the resulting residue was chromatographed over silica gel toobtain 4.5 g (yield 80%) of 2-(4-methoxybenzoyl)-2-azabicyclo[4, 4,0]decane-3-one (Compound 1) from hexane-ethyl acetate (3:1) eluate.Table 1 shows melting point and yield of the compound.

Reference Example 2

Compound 2 was obtained in the same manner as in Reference Example 1with use of, as a starting material, 2-azabicyclo [3, 3, 0]octane-3-one[Yakugaku Zasshi, 84, 674 (1964)]. Table 1 shows melting point and yieldof the compound.

Reference Example 3

A known compound, 2-azabicyclo[4, 3, 0]nonane-3-one was prepared by themethod discloses in Journal of American Chemical Society, 77, 409(1955).

Namely, to a solution of 50 ml (0.35 mol) of ethylcyclopentanone-2-carboxylate in 130 ml of dioxane was added 3.8 ml ofTriton B. Then, to the solution was added 27.1 ml (0.242 mol) ofacrylonitrile in 50 ml of dioxane. The solution was stirred at roomtemperature for 12 hours, and extracted with ether after 100 ml of 10%hydrochloric acid was added thereto. An organic layer was dried overanhydrous magnesium silfate. After removing the solvent, 300 ml of conc.hydrochloric acid was added to the residue and the mixture was heatedunder reflux for 24 hours. After cooling, the mixture was extracted withether and 5% aqueous solution of sodium hydroxide was added to the etherlayer and the mixture was stirred. An aqueous layer was made acidic withaddition of 10% hydrochloric acid, and then the mixture was extractedwith ethyl acetate. An organic layer was dried over anhydrous magnesiumsulfate. After removing the solvent, the residue was dissolved in 150 mlof ethanol and 10 ml of conc. sulfuric acid was added thereto. Themixture was heated under reflux for 14 hours, and then ethanol wasremoved therefrom after cooling, and ethyl acetate was added thereto.The mixture was washed with 10% aqueous solution of sodium hydroxide anddried over anhydrous magnesium sulfate. After removing the solvent, theresulting residue was chromatographed over silica gel to obtain 45 g(yield 70%) of ethyl 2-oxocyclopentanepropionate from hexane-ethylacetate (4:1) eluate. In 150 ml of 80% ethanol was dissolved 5.5 g (30mmol) of this compound. To the solution were added 4.17 g (60 mmol) ofhydroxylamine hydrochloride and 2.7 g (33 mmol) of sodium acetate andthe mixture was stirred at room temperature over night. After removingethanol, the mixture was extracted with ethyl acetate and dried overanhydrous magnesium sulfate. After removing the solvent, the resultingresidue was chromatographed over silica gel to obtain 5 g (yield 84%) ofethyl 2-hydroxyiminocyclopentanepropionate from hexane-ethyl acetate(6:1) eluate. In 15 ml of anhydrous ethanol was dissolved 4.4 g of thiscompound and the solution was stirred at 50° C. for 4 hours under ahydrogen pressure of 120 atm. with use of Raney nickel (W2) as acatalyst. After removing Raney nickel by filtration and removing thesolvent, the resulting residue was chromatographed over silica gel toobtain 0.95 g (yield 31%) of 2-azabicyclo[4, 3, 0]nonane-3-one fromethyl acetate eluate.

Compounds 3 to 10 were obtained in the same manner as in ReferenceExample 1 with use of the above compound as a starting material.

Reference Material 4

A known compound, 7-azabicyclo[4, 3, 0]nonane-8-one was prepared by themethod disclosed in Yakugaku Zasshi, 84, 674 (1964).

Namely, the desired 7-azabicyclo[4, 3, 0]nonane-8-one was prepared inthe same manner as in Reference Example 3, with use of, as a startingmaterial, ethyl 2-oxocyclohexyl acetate.

Compound 11 was obtained in the same manner as in Reference Example 1with use of the above compound as a starting material.

Reference Example 5

Compound 12 was obtained in the same manner as in Reference Example 1with use of, as a starting material, 8-azabicyclo [4, 3, 0]nonane-7-one(Journal of Chemical Society Perkin Transactions 1 11, 2563 (1982)).Table 1 shows melting point and yield of the compound.

In Table 1, Me and OMe for methyl and methoxy respectively.

                                      TABLE 1                                     __________________________________________________________________________                                 yield                                            No.                                                                              l m n R             m.p. (° C.)                                                                  (%)                                                                              formula                                       __________________________________________________________________________    1  2 0 2                                                                                ##STR7##     90˜91                                                                         80 C.sub.17 H.sub.21 NO.sub.3                    2  1 0 1                                                                                ##STR8##     63˜64                                                                         65 C.sub.15 H.sub.17 NO.sub.3                    3  1 0 2                                                                                ##STR9##     oil   80 C.sub.16 H.sub.19 NO.sub.3                    4  1 0 2                                                                                ##STR10##    79˜80                                                                         82 C.sub.16 H.sub.19 NO.sub.2                    5  1 0 2                                                                                ##STR11##    82˜83                                                                         90 C.sub.15 H.sub.15 NO.sub.2 Cl.sub.2           6  1 0 2                                                                                ##STR12##    78.5˜79.5                                                                     81 C.sub.17 H.sub.21 NO.sub.4                    7  1 0 2                                                                                ##STR13##    148.5˜149                                                                     83 C.sub.16 H.sub.16 N.sub.2 O.sub.2             8  1 0 2                                                                                ##STR14##    148˜149                                                                       85 C.sub.15 H.sub.16 N.sub.2 O.sub.4             9  1 0 2                                                                                ##STR15##    132˜134                                                                       65 C.sub.15 H.sub.18 N.sub.2 O.sub.2.  1/7                                       H.sub.2 O                                     10 1 0 2                                                                                ##STR16##    100˜101                                                                       90 C.sub.15 H.sub.16 NO.sub.2 Cl                 11 2 0 1                                                                                ##STR17##    oil   79 C.sub.16 H.sub.19 NO.sub.3                    12 2 1 0                                                                                ##STR18##    67˜69                                                                         52 C.sub.16 H.sub.19 NO.sub.3                    __________________________________________________________________________

Reference Example 6

Preparation of 6-oxo-bicyclo[3, 3, 0]octan-2-one-ethylene-acetal(Compound B)

A 9.62 g quantity of bicyclo[3, 3, 0]octan-2,6-dione (Compound A), 0.265g of p-toluenesulfonic acid monohydrate and 4.54 g of ethylene glycolwere dissolved in 50 ml of benzene, and the mixture was refluxed forreaction for 6 hours while removing water as an azeotropic mixture.After the reaction, the mixture was cooled to room temperature andallowed to stand for 15 minutes with addition of 3 g of sodiumhydrogencarbonate. The resulting precipitate was filtered off and washedwith benzene. The filtrate was concentrated to obtain a brown oilyproduct, which was purified by column chromatography using 180 g ofsilica gel and hexane-ethyl acetate (5:1) to obtain 9.28 g of Compound Bmentioned above in the form of a colorless oily substance (yield: 73%).¹ H-NMR (CDCl₃)δppm: 180˜2.45 (m, 10H). 3.95 (s, 4H)

Reference Example 7

Preparation of γ-1,t-2-hydroxybicyclo[3.3.0]octan-6-one =ethylene=acetal(Compound C)

A 9.23 g quantity of Compound B obtained in Reference Example 6 wasdissolved in 70 ml of methanol, and 1.93 g of sodium boron hydride wasadded to the solution while cooling the solution in an ice-methanolbath. The mixuture was returned to room temperature 30 minutes later,followed by further reaction for 1 hour. The methanol was thereafterdistilled off, 70 ml of water was added to the residue, and the mixturewas subjected to extraction with 100 ml of dichloromethane and 50 ml ofdichloromethane twice. The dichloromethane layer obtained was washedwith 50 ml of saturated aqueous sodium chloride solution, then driedover anhydrous sodium sulfate and distilled for the removal of solvent,giving a colorless oily product. The product was purified by columnchromatography using 150 g of silica gel and hexane-ethyl acetate (4:1to 2:1) to obtain 6.63 g of Compound C mentioned above in the form of acolorless oily substance (yield: 71%). ¹ H-NMR (CDCl₃) δ ppm : 1.75˜2.00(m, 8 H), 2.10˜2.80 (m, 2 H), 3.90˜4.18 (m, 1 H), 3.94 (s, 4 H)

Reference Example 8

Preparation ofγ-1,c-2-(4-nitrobenzoyloxy)bicyclo-[3.3.0]octan-6-one=ethylene=acetal(Compound D)

A 3.68 g quantity of Compound C obtained in Reference Example 7, 6.68 gof p-nitrobenzoic acid and 10.5 g of triphenylphosphine were dissolvedin 70 ml of tetrahydrofuran, and a solution of 7.00 g of diethylazodicarboxylate in 10 ml of tetrahydrofuran was added dropwise to thesolution with ice cooling over a period of 10 minutes. The mixture wasstirred with ice cooling for 1 hour, then returned to room temperatureand further reacted for 16 hours. The solvent was distilled off from thereaction mixture, 50 ml of ether and 30 ml of hexane were added to theresidue, and the resulting mixture was allowed to stand in arefrigerator for 1 day. The resulting precipitate (triphenylphosphineoxide) was filtered off and washed with hexane-ether (2:1). The filtrateobtained was concentrated to obtain a yellow oily product. The productwas purified by column chromatography using 90 g of silica gel, hexaneand hexane-ethyl acetate (10:1), giving 5.34 g of Compound D mentionedabove in the form of a light yellow oily substance (yield: 80%). ¹ H-NMR(CDCl₃) δ ppm : 1.60˜2.20(m, 8 H), 2.45˜2.90(m, 2 H), 3.94(s, 4 H),5.10˜5.23(m, 1 H), 8.24(s, 4 H)

Reference Example 9

Preparation of γ-1,c-2-hydroxybicyclo[3.3.0]octan-6-one=ethylene=acetal(Compound E)

A 12.85 g quantity of Compound D obtained in Reference Example 8 wasdissolved in 100 ml of methanol, 15 g of an anion exchange resin,Amberlite IR400 (OH--) (product of Organo Co., Ltd.), was added to thesolution, and the mixture was refluxed for 8 hours. Since the startingmaterial still remained, 10 g of the anion exchange resin was furtheradded to the mixture, followed by refluxing for 16 hours. The reactionmixture was returned to room temperature, filtered under High FlowSupercell (product of Nacalai Tesque Co., Ltd.) and washed withmethanol. Filtration gave a filtrate, which was concentrated andpurified by column chromatography using 100 g of silica gel andhexane-ethyl acetate (3:1), whereby 6.52 g of Compound E above-mentionedwas obtained as a colorless oily substance (yield: 92%). ¹ H-NMR (CDCl₃)γ ppm : 1.20˜2.15(m, 8 H), 2.30˜2.80(m, 2 H), 3.80˜4.10(m, 1 H), 3.91(s,4 H)

Reference Example 10

Preparation ofγ-1,c-2-benzyloxybicyclo[3.3.0]-octan-6-one=ethylene=acetal (Compound F)

A 6.40 g quantity of Compound E obtained in Reference Example 9 wasdissolved in 40 ml of N,N-dimethylformamide, 2.08 g of 60% sodiumhydride was added to the solution, and the mixture was stirred at roomtemperature. The reaction temperature rose to about 45° C. withevolution of hydrogen. One hour later, the reaction mixture was cooledwith ice, followed by addition of 6.3 ml of benzyl bromide. The mixturewas returned to room temperature 30 minutes thereafter and stirred for24 hours, followed by further reaction on a bath of 70° C. for 4 hours.The mixture was returned to room temperature, and 80 ml of ice water wasadded thereto. The resulting mixture was subjected to extraction with 60ml of ether three times. The ethereal layer was washed with 20 ml ofwater three times and with 20 ml of saturated aqueous solution of sodiumchloride and thereafter dried over anhydrous sodium sulfate. Removal ofthe solvent from the layer gave an oily product, which was then purifiedby column chromatography using 75 g of silica gel, and hexane andhexane-ether (15:1), whereby 6.65 g of Compound F mentioned above wasobtained as an oily substance (yield: 70%). ¹ H-NMR (CDCl₃) γ ppm :1.60˜2.10(m, 8 H), 2.40˜2.80(m, 2 H), 3.50˜3.80(m, 1 H), 3.90(s, 4 H),4.92(s, 2 H), 7.31(s, 5 H)

Reference Example 11

Preparation of γ-1,c-2-benzyloxybicyclo[3.3.0]-octan-6-one (Compound G)

A 1.94 g quantity of Compound F obtained in Reference Example 10 wasdissolved in 10 ml of tetrahydrofuran, and the solution was stirred for6 hours with 3 ml of 2 N hydrochloric acid added thereto. Thetetrahydrofuran was distilled off from the resulting reaction mixture,followed by extraction with 20 ml of ether twice. The ethereal layer waswashed with 10 ml of saturated aqueous solution of sodiumhydrogencarbonate twice and then with 5 ml of saturated aqueous solutionof sodium chloride, and dried over anhydrous sodium sulfate. Removal ofthe solvent from the layer give 1.60 g of Compound G mentioned above asan oily substance (yield: 98%). ¹ H-NMR (CDCl₃) γ ppm : 1.30˜2.40(m, 8H), 2.60˜3.00(m, 2 H), 3.70˜3.90(m, 1 H), 4.51(s, 2 H), 7.33(s, 5 H)

Reference Example 12

Preparation of γ-6,c-7-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3-one (Compound Ja) andγ-6,c-7-benzyloxy-3-(4-methoxybenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one(Compound Jb)

A 1.54 g quantity of Compound G obtained in Reference Example 11 wasdissolved in 15 ml of tetrahydrofuran, followed by addition of 8 ml ofwater and thereafter by addition of 0.94 g of hydroxylaminehydrochloride and 1.84 g of sodium acetate trihydrate. Tetrahydrofuranwas subsequently added to obtain a homogeneous mixture, which was thenstirred at room temperature for 5 hours. The tetrahydrofuran wasdistilled off from the reaction mixture, followed by extraction with 80ml of ethyl acetate. The ethyl acetate layer was washed with 10 ml ofwater, with 10 ml of saturated sodium hydrogencarbonate solution andsubsequently with 10 ml of saturated aqueous solution of sodiumchloride, and thereafter dried over anhydrous sodium hydrogen sulfate.Distillation of the layer for the removal of the solvent gave 1.64 g ofoxime of Compound G as a colorless oily substance.

A 1.60 g of the oxime obtained was dissolved in 16 ml of benzene,followed by addition of 3.11 g of p-toluenesulfonyl chloride and then byadditoin of 2.27 ml of triethylamine with ice cooling. The mixture wasstirred for 4 hours with ice cooling and subsequently for 2 hours atroom temperature, and thereafter diluted with 50 ml of ether. Theresulting solution was washed with 10 ml of water, with 10 ml of 2 Nhydrochloric acid twice and subsequently with 10 ml of saturated aqueoussolution of sodium chloride, and thereafter dried over anhydrous sodiumsulfate. Removal of the solvent from the solution gave a yellow oilyproduct. The product was dissolved in 50 ml of anhydrous benzene,followed by addition of 43 g of silica get (Fuji Silysia Chemical Ltd.,BW-300 as washed with 2 N HCl and then thoroughly with water, and driedat 230° C. for 16 hours) and further by addition of anhydrous benzene inan amount of permitting stirring of the resulting mixture. The mixturewas shaken on a water bath having a constant temperature of 25° C. for18 hours. The reaction mixture was poured into a column packed with 20 gof silica gel, and 300 ml of benzene was passed through the column tocause an excess of p-toluenesulfonyl chloride to flow out. The solventwas thereafter changed for benzene-methanol (6:1) to obtain an eluate.The eluate still contained impurities and was therefore purified bycolumn chromatography again using 30 g of silica gel, and chloroform andchloroform-methanol (50:1). The product was dried in a vacuum at roomtemperature to obtain 1.233 g of a light yellow oily substance. PRManalysis revealed that the product was a mixture ofγ-6,c-7-benzyloxy-2-azabicyclo [4.3.0]nonan-3-one (Compound Ha) andγ-6,c-7-benzyloxy-3-azabicyclo [4.3.0]nonan-2-one (Compound Hb)approximately in the ratio of 2:1.

The mixture (1.18 g) obtained was dissolved in 15 ml of dichloromethane,1.31 g of p-methoxybenzoyl chloride and 1.34 g of triethylamine wereadded to the solution, and the mixture was stirred at room temperaturefor 36 hours. With addition of 80 ml of ethyl acetate, the reactionmixture was washed with 20 ml of 2 N hydrochloric acid twice, with 20 mlof saturated solution of sodium hydrogencarbonate twice and then with 10ml of saturated aqueous solution of sodium chloride, and dried overanhydrous sodium sulfate. Removal of the solvent gave a brown oilyproduct, which was then purified by column chromatography using 30 g ofsilica gel and hexane-ethyl acetate (4:1 to 3:1). The compound elutedfirst was Compound Jb mentioned above and obtained in an amount of 0.576g as a yellow oily substance (yield: 25%). The component elutedthereafter was Compound Ja mentioned above. The fraction was distilledfor the removal of the solvent and recrystallized from ethanol, giving1.05 g of the compound (yield: 46%).

Characteristic Values of Compound Ja

m.p. (in ethanol solvent): 108.5˜109.5° C.

¹ H-NMR (CDCl₃) δ ppm: 1.30˜2.70(m, 10 H), 3.70˜4.00(m, 1 H), 3.83(s, 3H), 4.54(s, 2 H), 6.87(d, 2 H), 7.34(s, 5 H), 7.58(d, 2 H)

Characteristic Values of Compound Jb

¹ H-NMR (CDCl₃) δ ppm: 1.30˜3.30(m, 10 H), 3.60˜4.10(m, 1 H), 3.83(s, 3H0, 4.52(s, 2 H), 6.86(d, 2 H), 7.33(s, 5 H), 7.54(d, 2 H)

Reference Example 13

γ-6,c-7-Hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo [4.3.0]nonan-3-one(Compound 13)

A 1.05 g quantity of Compound Ja obtained in Reference Example 12 wasdissolved in 15 ml of dioxane, 0.50 g of 10% palladium carbon (productof Wako Junyaku Co., Ltd.) was added to the solution, and the air in thereactor was removed by an aspirator and replaced by hydrogen repeatedlytwice. The mixture was thereafter stirred in the hydrogen atmosphere (1atm.) for 16 hours. The catalyst was filtered off and washed withdioxane. The resulting filtrate was concentrated to obtain a colorlessoily product, which was then purified by column chromatography using 15g of silica gel and chloroform. Removal of the solvent from the productafforded crystals, which were further recrystallized from ether, giving0.64 g of Compound 13 mentioned above in the form of a colorless powder(yield: 81%). m.p. (in diethyl ether solvent): 120˜121° C. ¹ H-NMR(CDCl₃) δ ppm: 1.20˜2.70(m, 10 H), 3.84(s, 3 H), 3.90˜4.30(m, 1 H),4.20(q, 1 H), 6.88(d, 2 H), 7.59(d, 2 H)

Example

    ______________________________________                                        Tablet                                                                        ______________________________________                                        Compound 1              30 mg                                                 Microcrystalline cellulose                                                                            50 mg                                                 Hydroxypropyl cellulose 20 mg                                                 Lactose                 47 mg                                                 Talc                    2 mg                                                  Magnesium stearate      1 mg                                                  ______________________________________                                    

By the usual method, the above ingredients in the proportions given weremade into tablets each weighing 150 mg.

Example 2

    ______________________________________                                        Granule                                                                       ______________________________________                                        Compound 3               10 mg                                                Lactose                  400 mg                                               Corn starch              370 mg                                               Hydroxypropyl cellulose  20 mg                                                ______________________________________                                    

The above ingredients in the proportions given were made into a granularpreparation by the usual method in an amount of 800 mg per wrapper.

Example

    ______________________________________                                        Capsule                                                                       ______________________________________                                        Compound 11             55 mg                                                 Lactose                 50 mg                                                 Corn starch             50 mg                                                 Microcrystalline cellulose                                                                            94 mg                                                 Magnesium stearate      1 mg                                                  ______________________________________                                    

By the usual method, the above ingredients in the proportions given weremade into a capsule in an amount of 250 mg in each capsule.

Example 4

    ______________________________________                                        Injection                                                                     ______________________________________                                        Compound 13           10 mg                                                   Sodium chloride       3.5 mg                                                  Distilled water for injections,                                                                     suitable amount                                         ______________________________________                                    

The above ingredients in the proportions given were made into aninjection by the usual method.

Example

    ______________________________________                                        Syrup                                                                         ______________________________________                                        Compound 3            50 mg                                                   Purified sucrose      60 g                                                    Ethyl para-hydroxybenzoate                                                                          5 mg                                                    Butyl para-hydroxybenzoate                                                                          5 mg                                                    Perfume               suitable amount                                         Coloring agent        suitable amount                                         Purified water        suitable amount                                         ______________________________________                                    

The above ingredients in the proportions given were made into a syrup bythe usual method.

Example

    ______________________________________                                        Suppositories                                                                 ______________________________________                                        Compound 11           50 mg                                                   Witepsol W-35         1400 mg                                                 ______________________________________                                    

(Trademark, a mixture of mono-, di and triglyceride of saturated fattyacids from lauric acid to stearic acid, Dynamite Mobel Co., Ltd.)

By the usual method, the above ingredients in the proportions given weremade into suppositories.

Test Example 1 Anticonflict Test

1. Expermental animals

Wistar rats (males weighing 140 to 160 g) were used for experiment ingroups of 11 to 14.

2. Test agents and administration method

The test compound, diazepam or buspirone was suspended in a 0.5% sodiumcarboxymethyl cellulose solution, and the suspension was orally given tothe animal in a volume of 5 ml/kg one hour before the start ofexperiment.

3. Experimental method and result

With reference to a method described in "Process in Anxiolytics andAntidepressants," edited by Showa Ueki and Tatsuo Furukawa, IshiyakuShuppansha, 56˜59 (1981), the agents were tested using experimentalboxes having a grid floor and a metal drinking tube in the floor. Nowater was supplied to the rats for 48 hours before the experiment. Uponlapse of first 24 hours, each group of rats were placed into theexperimental box, permitted access to water for 30 seconds and caused torecognize the metal drinking tube. Upon lapse of further 24 hours withaccess to water prevented, the rats were placed into the box again andpermitted access to water on condition that an electric current waspassed between the metal drinking tube and the grid to give anelectroshock for every 20 times of water drinking behavior to measurethe frequency of water drinking behavior for 3 minutes. Table 2 showsthe result. Compound 1, 3, 11 and 13 exhibited an increase in thefrequency of water drinking behavior at doses of 0.001 to 1.0 mg/kg,producing an anxiolytic effect, but diazepam and buspirone were foundalmost ineffective.

                  TABLE 2                                                         ______________________________________                                        Anticonflict Test                                                                         Dose    Frequency of water drinking                               Test compound                                                                             (mg/kg) behavior (times/3 min)                                    ______________________________________                                        Control             100                                                       Compound 1  0.01    138                                                                   0.1     140                                                                   1.0     122                                                       Compound 3  0.001   126                                                                   0.01    162                                                                   0.1     164                                                                   1.0     166                                                       Compound 11 1.0     133                                                       Compound 13 0.001   130                                                                   0.01    183                                                                   0.1     177                                                                   1.0     169                                                       Diazepam    1.0     96                                                        Buspirone   1.0     103                                                       ______________________________________                                    

The frequency is expressed by a value relative to the frequency of thecontrol which is taken as 100.

Test Example 2 Elevated Plus Maze Test

1. Exaperimental animals

Wistar rats (males weighing 170 to 220 g) were used for experiment ingroups of 4 to 9.

2. Test agents and administration method

The test compound, diazepam or buspirone was suspended in a 0.5% sodiumcarboxymethyl cellulose solution, and the suspension was orally given tothe animal in a volume of 5 ml/kg one hour before the start ofexperiment.

3. Experimental method and result

The test was conducted using an experimental device, Model BTA-2,Behavior Analysis System (product of Muromachi Kikai Co., Ltd.) withreference to a method described in Psychopharmacology, 99, 48˜53(1989).The device had a maze comprising pairs of opposed open arms having noside walls and positioned at a level of about 50 cm above the floor,closed arms having side walls and a center square at an intersection.Each group of rats orally given the test drug were placed in the centersquare, and the behavior of the animals was recorded for 5 minutes usinga behavior analyzer. The ratio of the number of entries into the openarm to the number of entries into all the arms was determined forevaluating the anxiolytic effect. Table 3 shows the result. Compound 3achieved an increase in the number of entries into the open arm withlapse of time when taken at a dose of 0.001 mg/kg or greater, thusexhibiting an anxiolytic effect.

                  TABLE 3                                                         ______________________________________                                        Elevated Plus Maze Test                                                                               Ratio of entries                                      Test compound   Dose    into open arm                                         ______________________________________                                        Control                 100                                                   Compound 3      0.001   195                                                                   0.01    219                                                                   0.1     248                                                   Diazepam        1.0     103                                                                   10.0    144                                                   Buspirone       1.0     98                                                                    10.0    93                                                    ______________________________________                                    

The ration of entries into the open arm is expressed by a value relativeto the ratio attained by the control which is taken as 100.

Test Example Muscle Relaxant Effect (Traction Method)

1. Experimental Animals and Administration Method

Compound 3, Compound 13, diazepam or buspirone was suspended in a 0.5%sodium carboxymethyl cellulose solution, and the suspension was orallyadministered to 3- to 4-week-old male ddY mice (in groups of 5) in avolume of 10 ml/kg one hour before the start of experiment.

2. Experimental Method and Result

With reference to a method described in Japan. J. Pharmacol., 49.337˜349(1989), the foreleg of the mouse was hung on a horizontal wire,having a diameter of 1.2 mm and fixed at a level of 30 cm, three timesconsecutively. If the hind leg did not touch the wire within 10 secondseach time, the result was interpreted as positive. Thus, ED₅₀ wasdetermined for evaluation. Consequently, Compounds 3 and 13 exhibited nomuscle relaxant effect even when given at a dose of 300 mg/kg. Diazepamand buspirone were 2.2 mg/kg and 427.8 mg/kg, respectively, in ED₅₀.

Test Example 4 Sedative Effect (Spontaneous Locomotor Activity)

1. Experimental Animals and Administration Method

Compound 3, Compound 13 diazepam or buspirone was suspended in a 0.5%sodium carboxymethyl cellulose solution, and the suspension was orallyadministered to 3- to 4-week-old male ddY mice (in groups of 5) in avolume of 10 ml/kg one hour before the start of experiment.

2. Experimental Method and Result

The test was conducted with reference to a method described in"Evaluation of Medicinal Efficacies (1), Pharmacological Test Method(1), Basic Lectures on Development of Pharmaceuticals," 50˜54(1971).More specifically, the group of mice were given the test drug andthereafter measured the amount of spontaneous locomotor activity for 10minutes per mouse using Animex MK-110 (product of Muromachi Kikai Co.,Ltd.). When the amount of activity was up to 50% of the control group,the result was interpreted as positive to determine Ed₅₀ for evaluation.Consequently, Compounds 3 and 13 exhibited no sedative effect even at adose of 300 mg/kg. Diazepam and buspirone were 1.7 mg/kg and 149.7mg/kg, respectively, in the above value.

Test Example 5 Effect on Central Nervous System Depressant

a. Pentobarbital Anesthetic Method

1. Experimental animals and administration method

Compound 3, Compound 13, diazepam or buspirone was suspended in a 0.5%sodium carboxymethyl cellulose solution, and the suspension was orallyadministered to 3- to 4-week-old male ddY mice (in groups of 5 to 10) ina volume of 10 ml/kg one hour before the start of experiment.

2. Experimental method and result

The test was conducted with reference to a method described in"Evaluation of Medicinal Efficacies (1), Pharmacological Test Method(I), Basic Lectures on Development of Pharmaceuticals," 144˜145(1971).More specifically, the group of mice were intraperitoneally givenpentobarbital at a dose of 40 mg/kg and checked for sleeping time. Whenthe sleeping time was in excess of twice that of the control group, theresult was interpreted as positive to determine ED₅₀ for evaluation.Consequently, Compound 3 was at least 300 mg/kg, and Compound 13 was224.5 mg/kg in this value. Diazepam and buspirone were 0.53 mg/kg and91.7 mg/kg, respectively, in the value.

b. Ethanol Enhancing Method

1. Experimental animals and administration method

Compound 3, Compound 13, diazepam or buspirone was suspended in a 0.5%sodium carboxymethyl cellulose solution, and the suspension was orallyadministered to 3- to 4-week-old male ddY mice (in groups of 6) in avolume of 10 ml/kg one hour before the start of experiment.

2. Experimental method and result

The test was conducted with reference to a method described in Japan. J.Pharmacol., 49, 337˜349(1989). More specifically, the group of micewerre intraperitoneally given 25% ethanol at a dose of 20 ml/kg andchecked for the time interval between loss and recovery of the rightingreflex. When the time measurement was in excess of twice the measurementof the control group, the result was interpretated as positive todetermine ED₅₀ for evaluation. Consequently, Compounds 3 and 13 producedno ethanol enhancing effect even at a dose of 300 mg/kg. Diazepam andbuspirone were 0.48 mg/kg and 120.1 mg/kg, respectively, in the value.

Test Example 6 Anticonvulsant Effect (Pentylenetetrazol-InducedConvulsion Method)

1. Experimental Animals and Administration Method

Compound 3, Compound 13, diazepam or buspirone was suspended in a 0.5%sodium carboxymethyl cellulose solution, and the suspension was orallyadministered to 3- or 4-week-old male ddY mice (in groups of 6) in avolume of 10 ml/kg one hour before the start of experiment.

2. Experimental Method and Result

The test was conducted with reference to a method described in"Evaluation of Medicinal Efficacies (1), Pharmacological Test Method(I), Basic Lectures on Development of Pharmaceuticals," 167˜172(1971).More specifically, pentylenetetrazol was subcutaneously administered tothe mouse at a dose of 150 mg/kg, and when the mouse did not die due toonset of convulsion within 60 minutes, the result was interpretated aspositive to determine ED₅₀ for evaluation. Consequently, Compounds 3 and13 exhibited no anticonvulsant effect even at a dose of 300 mg/kg.Diazepam and buspirone were 0.35 mg/kg and at least 300 mg/kg,respectively, in the value.

Test Example 7 Acute Toxicity Test

Five-week-old male ddY mice were used in groups of 4 to 5. The mice wereorally given the test compound as suspended in a 0.5% sodiumcarboxymethyl cellulose solution and thereafter observed for 3 days tomeasure the number of deaths and determine Ed₅₀. Table 4 shows theresult.

                  TABLE 4                                                         ______________________________________                                        Acute Toxicity Test                                                                          Acute Toxicity                                                 Test compound  LD.sub.50 (mg/kg)                                              ______________________________________                                        Compound 1     2000<                                                          Compound 3     2000<                                                          Compound 11    2000<                                                          Compound 13    3000<                                                          ______________________________________                                    

INDUSTRIAL APPLICABILITY

The anxiolytic agent comprising a bicyclolactam derivative representedby the formula (1) as its effective component has a high anxiolyticeffect, is reduced in side effects such as sedative, muscle relaxant,hypnotic and anticonvulsant effects and is low in toxicity. Accordingly,the agent of the present invention is useful for treating or preventingchronic or acute anxiety disorders (or anxiety and fear neuroses), suchas panic disorder accompanied or not accompanied by agoraphobia, socialphobia or simple phobia, obsessive-compulsive disorder (neurosis),stress disorder resulting from injury and systemic anxiety disorder, andother anxiety disorders, and also for relieving healthy persons and theaged of anxiety.

Additionally, the present invention is useful for treating or preventingthe anxiety attendant on withdrawal symptoms due to drug dependanceand/or drug addiction. Thus, the present invention is useful forallaying withdrawal symptoms due to alcohol dependence, nicotinedependence, cocaine dependence and benzodiazepine dependence andwithdrawal symptoms due to other drug dependence.

The present invention also relates to a novel bicyclolactam compound,use thereof and an intermediate for preparing the bicyclolactamcompound. The present compound has an excellent anxiolytic effect and isuseful as an anxiolytic agent.

The compounds which are similar to the bicyclolactam compounds of thepresent invention are disclosed in International Publication No. WO91/11434, and are known to have a cerebral function improving effect,cerebral metabolism activating or anoxic brain damage protecting effectand effect against senile dementia. The present compound differs fromthose disclosed in WO 91/11434 in that the former has a substituent ringdirectly attached to a carbon atom on the bicyclo ring.

Further, when the compound disclosed in International Publication No. WO91/11434 is orally administered, a lot of metabolites are produced. Thiscauses an administration of non-effective substances and is unsuitableto develop pharmaceuticals. The present compound produces less amount ofmetabolites and is high in safety.

An object of the present invention is to provide a novel bicyclolactamcompound and an intermediate for production of the bicyclolactamcompound. The bicyclolactam compound has an excellent anxiolytic effect,is high in safety and is useful as an effective component of medicinalswhich are greatly diminished in side effects such as hypnotic, musclerelaxant and sedative effects.

DISCLOSURE OF THE INVENTION

The present invention provides a bicyclolactam compound represented bythe following formula (1) ##STR19## wherein R is oxo or --OR¹, R¹ is ahydrogen atom or acyl group, A is a group of (2) or (3), Q is a hydrogenatom or lower alkyl group, l is 1 or 2, m is 0 or 1 and n is 0, 1 or 2,provided the case where both of m and n represent 0 simultaneously isexcluded ##STR20## wherein R² is benzoyl group or substituted benzoylgroup.

The present invention also provides a bicyclolactam compound representedby the following formula (4) ##STR21## wherein A, Q, l, m and n are asdefined above, R³ is benzyl group or substituted benzyl group.

The present invention further provides a process for preparing abicyclolactam compound represented by the following formula (1'),comprising replacing R³ in the bicyclolactam compound of the formula (4)by hydrogen atom in a suitable solvent in the presence of a catalyst##STR22## wherein A, Q, l, m and n are as defined above.

The present invention further provides a process for preparing abicyclolactam compound represented by the following formula (1'),comprising acylating the bicyclolactam compound of the formula (1') in asuitable solvent ##STR23## wherein A, Q, l, m and n are as definedabove, R¹ is acyl group.

The present invention further provides a process for preparing abicyclolactam compound represented by the following formula (1'"),comprising reacting a compound of the formula (5) and a bicyclolactamcompound of the formula (6) in a suitable solvent in the presence of abase

    R.sup.2 --X                                                (5)

wherein R² is as defined above, X is a halogen atom, ##STR24## wherein Qand l are as defined above, ##STR25## wherein R², Q and l are as definedabove.

The present invention further provides a pharmaceutical compositioncomprising an effective amount of the above bicyclolactam compound and apharmaceutically acceptable carrier.

The present invention further provides an anxiolytic agent comprising aneffective amount of the above bicyclolactam compound and apharmaceutically acceptable carrier.

The present invention further includes a method of treating anxietycomprising administering an effective amount of the above bicyclolactamcompound to mammals including man, and also use of the abovebicyclolactam compound for the preparation of medicinals for treatinganxiety.

The bicyclolactam compound of the formula (1) has an excellentanxiolytic effect, is high in safety, diminished in side effects, anduseful as medicinals. Further, the bicyclolactam compound of the formula(4) is useful as an intermediate for preparing the bicyclolactamcompound of the formula (1).

Existing as bicyclolactam derivatives of the formula (1) or (4) arestereoisomers due to the presence of the bicyclo ring, and alsogeometric isomers and optical isomers due to the presence of the carbonatom at the bridgehead position of the bicyclo ring and the carbon atomhaving R¹ O-- or R³ O-- attached thereto. The present invention includesall of these isomers.

In view of the numbers l, m and n, the following fourteen (14) kinds ofbicyclo ring skeletons can be present in the compounds of the formula(1) or (4). The invention includes all of these cases. ##STR26##

Preferable among these is the case wherein m or n is 0, i.e. theskeleton (a), (b), (c), (f), (g), (h), (k) or (m). More preferable isthe case wherein l is 1, m is 0, n is 2, i.e., (b) or (k).

In the present invention, in the case where the substituent R is oxogroup, the bond between R and the carbon on the bicyclo ring showsdouble bond.

In case of, for example, the above bicyclolactam ring skeleton (a), thefollowing three positions are shown where the substituent R of thecompound of the formula (1) [or --OR³ of the compound of the formula(4)] attaches to the bicyclolactam ring. Although the invention includesall of these cases, preferable is (p) or (r) below where R (or --OR³)attaches to the vicinal carbon atom of the brigehead atom of thebicyclolactam ring. This is similar in the other bicyclolactam ringskeletons (b) to (n). ##STR27##

According to the invention, examples of benzoyl groups which mayoptionally have at least one substituent represented by R² are benzoylgroups which may optionally have, as a substituent, a halogen atom,lower alkyl group, lower alkoxyl group, nitro group, cyano group,hydroxyl group or amino group. Preferable are those which may optionallyhave, as a substituent, a halogen atom, lower alkyl group or loweralkoxyl group. More preferable is that which has, as a substituent, atleast one lower alkoxyl group. The number of substituents is preferably1 to 3. The substituent may be present at any of the ortho-, meta - andpara-positions on the phenyl ring of the benzoyl group. Examples ofbenzyl groups which may optionally have at least one substituentrepresented by R³ are benzyl groups which may optionally have on thephenyl ring, as a substituent, 1 to 3 of lower alkyl group, loweralkoxyl group, halogen atom or trifluoromethyl group. Preferably isunsubstituted benzyl group. Examples of halogen atoms are fluorine,chlorine, bromine and iodine atom, among which fluorine atom ispreferable. Examples of useful lower alkyl groups are straight-chain orbranched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyland hexyl group. Preferable among these is methyl or ethyl group. Methylgroup is more preferable. Examples of useful lower alkoxyl groups arestraight-chain or branched alkoxyl group having 1 to 6 carbon atoms,such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy group,among which methoxy or ethoxy group is preferable. Methoxy group is morepreferable.

Acyl groups represented by R¹ and R^(1a) include widely an aliphaticacyl group and aromatic acyl group. Examples of aliphatic acyl groupsare those having 2 to 6 carbon atoms, such as formyl, acetyl, propionyl,butyryl, isobutyryl, pentanoyl, hexanoyl, acryloyl, propioloyl,methacryloyl and crotonoyl. Examples of aromatic acyl groups arebenzoyl, 3-tolouyl, 4-toluyl, 2-methoxybenzoyl, 2,4-dimethoxybenzoyl,α-naphthylcarbonyl and β-naphthylcarbonyl. Preferable among these isacetyl or benzoyl group. Acetyl group is more preferable.

Lower alkyl group shown by Q includes the above lower alkyl groups,among which methyl and ethyl groups are preferable. Methyl group is morepreferable.

Halogen atom shown by X includes the above halogen atoms, among whichchlorine atom is preferable.

Among the compounds of the formula (1) or (4), preferable are thosehaving a ring structure wherein m or n is 0 [provided m and n are not 0(zero) simultaneously], and more preferable are those wherein l is 1, mis 0 and n is 2. In case of the compound (1) wherein R is --OR¹,preferable are those wherein R¹ is a hydrogen atom or acetyl group, R²is benzoyl or benzoyl having lower alkoxyl group, halogen atom or loweralkyl group, Q is a hydrogen atom, and wherein l is 1, m is 0 and n is2. Especially preferable are those wherein R¹ is a hydrogen atom, R² isa benzoyl having methoxy group, Q is a hydrogen atom, and wherein l is1, m is 0 and n is 2.

Among the compounds of the formula (1) wherein R is oxo group,preferable are those wherein R² is a benzoyl or benzoyl having loweralkoyl group or lower alkyl group, Q is a hydrogen atom or lower alkylgroup, and wherein l is 1, m is 0 and n is 2. Especially preferable arethose wherein R² is benzoyl having methoxy or methyl group, Q is ahydrogen atom or methyl group, and wherein l is 1, m is 0 and n is 2.

Further, in case of the compound (4), preferable are those wherein R² isbenzoyl or benzoyl having lower alkoxyl group, halogen atom or loweralkyl group, R³ is benzyl group, Q is a hydrogen atom, and wherein l is1, m is 0 and n is 2. Especially preferable are those wherein R² is abenzoyl having methoxy group, Q is a hydrogen atom, and wherein l is 1,m is 0 and n is 2.

Example of the compound of the above formula (1) or (4) are7-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-2-benzoyl-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-2-(4-fluorobenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-2-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-3-(4-methoxybenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-benzyloxy-3-benzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-benzyloxy-3-(4-fluorobenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-benzyloxy-3-(p-toluoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-benzyloxy-3-(2,4-dimethoxybenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-benzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(4-fluorobenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-3-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-3-benzoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-3-(4-fluorobenzoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-3-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-3-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-acetoxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-acetoxy-2-benzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-acetoxy-2-(4-fluorobenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-acetoxy-2-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-acetoxy-2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-acetoxy-3-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-acetoxy-3-benzoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-acetoxy-3-(4-fluorobenzoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-acetoxy-3-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-2-one,7-acetoxy-3-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-2-one,6-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo-[3.3.0]octan-3-one,7-benzyloxy-3-benzoyl-3-azabicyclo-[3.3.0]nonan-2-one,8-benzyloxy-3-(4-fluorobenzoyl)-3-azabicyclo-[5.3.0]decan-2-one,2-benzyloxy-7-(p-toluoyl)-7-azabicyclo-[4.3.0]nonan-8-one,7-benzyloxy-2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.4.0]decan-3-one,2-benzyloxy-8-(4-methoxybenzoyl)-8-azabicyclo-[4.3.0]nonan-7-one,7-benzyloxy-3-benzoyl-3-azabicyclo-[4.4.0]decan-4-one,8-benzyloxy-3-(4-fluorobenzoyl)-3-azabicyclo-[5.4.0]undecan-4-one,9-benzyloxy-4-(p-toluoyl)-4-azabicyclo-[5.4.0]undecan-3-one,3-(4-methoxybenzoyl)-3-azabicyclo-[5.4.0]undecan-4,8-dione,2-(4-methoxybenzoyl)-2-azabicyclo-[4.4.0]decan-3,7-dione,2-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(3-ethylbenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(2-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(3-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(2,6-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(3,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(3,5-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(3,4,5-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,6-methyl-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione, and6-ethyl-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,

Preferable examples are7-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-2-benzoyl-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-2-(4-fluorobenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-2-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-benzyloxy-3-(4-methoxybenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-benzyloxy-3-(4-fluorobenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-benzyloxy-3-(p-toluoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-benzyloxy-3-(2,4-dimethoxybenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-benzoyl-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(4-fluorobenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-3-(4-methoxybenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-3-(4-fluorobenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-3-(p-toluoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-acetoxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(4-methylbenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(2-methoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(3-methoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(2,6-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(3,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(3,5-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione,2-(3,4,4-trimethoxybenzoyl)-2-azabicyclo-[4.3.0]decan-3,7-dione, and6-methyl-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,

More preferable examples are7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-benzoyl-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(4-fluorobenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one,7-hydroxy-3-(4-methoxybenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-3-(4-fluorobenzoyl)-3-azabicyclo-[4.3.0]nonan-2-one,7-hydroxy-3-(p-toluoyl)-3-azabicyclo-[4.3.0]nonan-2-one,2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(3-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(2,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(3,4-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,2-(3,5-dimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione, and2-(3,4,5-trimethoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione,

The bicyclolactam compound of the present invention wherein R is --OR¹can be prepared, for example, by the following reaction process##STR28## wherein Q, R², R³, l, m and n are as defined above, R^(1a) isacryl group, R⁴ is a hydrogen atom, lower alkyl group, lower alkoxylgroup, halogen atom or trifluoromethyl group, X is a halogen atom.

In the above, acyl a group represented by R^(1a) includes same acylgroups as above, lower alkyl group, lower alkoxyl group and halogen atomrepresented by R⁴ includes same ones as above, and halogen atom shown byX includes same ones as above.

(Step i) A known compound A obtained by the method disclosed in J. Org.Chem., 42, 3764≈3767 (1997), J. Chem. Soc., Chem. Commun., 24, 2759≈60(1994) or Chem. Lett., 9, 1437≈40 (1985) is reacted with ethylene glycolin a suitable solvent in the presence of an acid catalyst to obtain acompound B. The solvent to be used is not particularly limited insofaras it does not participate in the reaction; it is, for example, anaromatic hydrocarbon such as benzene, toluene or xylene. Examples ofuseful acid catalysts are sulfuric acid, p-toluenesulfonic acid,methanesulfonic acid, trifluoromethanesulfonic acid and the like. Thereaction is conducted using ethylene glycol and the acid catalyst eachin an amount of about 1 to about 2 moles per mole of the compound A. Thereaction temperature is 80° C. to a temperature around the boiling pointof the solvent. For the completion of the reaction, the reaction time is1 to 8 hours, preferable about 4 to about 7 hours. The compound Bobtained by the invention can be used for the subsequent reaction, asisolated or without being isolated.

(Step ii) Next, the compound B is reacted with a reducing agent in asuitable solvent to obtain a compound trans-C which has a hydroxyl groupin the trans-position to hydrogen atom attached to a bridgehead atom a.The solvent to be used is not limited specifically insofar as it doesnot participate in the reaction. Examples of such solvents are methanol,ethanol, propanol, isopropanol and like alcohols, dioxane,1,2-dimethoxyethane, tetrahydrofuran and like ethers. Examples of usefulreducing agents are lithium aluminum hydride, diisobutyl aluminumhydride, diborane, sodium boron hydride and the like. The reaction isconducted using the reducing agent in about 1 to about 1.5 moles permole of the compounds. The reaction temperature is -5° C. to roomtemperature, preferably about 0 to about 10° C. The reaction time ispreferably about 1 to bout 3 hours. The compound trans-C resulting fromthe reaction can be used for the subsequent reaction (Step iii) or (Stepv), as isolated or without being isolated.

(Step iii) The compound trans-C is reacted with p-nitrobenzoic acid,triphenylphosphine and diethyl azodicarboxylate in a suitable solvent toobtain a compound D. The solvent to be used is not limited specificallyinsofar as it does not participate in the reaction. Examples of suchsolvents are dioxane, 1,2-dimethoxyethane, tetrahydrofuran and likeethers, chloroform, dichloromethane, dichloroethane and like hydrocarbonhalides. The reaction is conducted using the latter three reactants eachin about 1 to about 3 moels per mole of the compound trans-C. Thereaction temperature is -5 to 50° C., preferably about 0° C. to aroundroom temperature. The reaction times is 1 to 15 hours, preferably about6 to about 12 hours. The compound D resulting from the reaction can beused for the subsequent reaction, as isolated or without being isolated.

(Step iv) The compound D is hydrolyzed in a suitable solvent with use ofan anion exchange resin to obtain a compound cis-C which has a hydroxylgroup in the cis-position to hydrogen atom attached to a bridgehead atoma. The solvent to be used is not limited specifically insofar as it willnot participate in the reaction. Examples of such solvents are methanol,ethanol, propanol, isopropanol and like alcohols. The reaction isconducted using the anion exchange resin in about 1 to about 10 molesper mole of the compound Cis-D. The reactions temperature is roomtemperature to 100° C., and the reaction time is about 10 to about 24hours. The compound cis-C resulting from the reaction can be used forthe subsequent reaction, as isolated or without being isolated.

(Step v) The compound C obtained in (Step ii) or (Step iv) is reactedwith a known compound E in a suitable solvent in the presence of a baseto obtain a compound F. The solvent to be used is not limitedspecifically insofar as it does not participate in the reaction.Examples of such solvents are N,N-dimethylformamide,N,N-dimethylacetamide, acetonitrile and like aprotic polar solvents,dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers. Examplesof useful bases are trimethylamine, trimethylamine, pyridine and liketertiary amines, potassium carbonate, sodium carbonate and like alkalimetal carbonate, and potassium hydride, sodium hdyride and like alkalimetal hydrides. For the reaction, the base and compound E are used eachin about 1 to about 2 moles per mole of the compound C. The reactiontemperature is room temperature to 100° C., preferably room temeratureto about 70° C. The reaction time is 8 to 30 hours, preferably about 20to about 28 hours. The compound F resulting from the reaction can beused for the subsequent reaction, as isolated or without being isolated.

(Step vi) The compound F is subjected to a ketal removing reaction in asuitable solvent with use of an acid to obtain a compound G. The solventis not limited specifically insofar as it does not participate in thereaction. Examples of solvents are alcohols such as methanol, ethanol,propanol and isopropanol, and ethers such as dioxane,1,2-dimethoxyethane and tetrahydrofuran. Examples of useful acids areacetic acid, trifluoroacetic acid, oxalic acid and like organic acids,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and likeinorganic acids. The reaction temperature is 0 to 60° C., preferablyabout 10 to about 70° C. The reaction time is about 2 to about 8 hours.The compound G resulting from the reaction can be used for thesubsequent reaction, as isolated or without being isolated.

(Step vii-a) The compound G is reacted with hydroxylamine and sodiumacetate in a suitable solvent to obtain an oxime of the compound G. Thesolvent is not limited specifically insofar as it does not participatein the reaction. Examples of useful solvents are methanol, ethanol,propanol, isopropanol and like alcohols, dioxane, 1,2-diemthoxyethane,tetrahydrofuran and like ethers. Hydroxylamne and sodium acetate areused each in about 1.5 to 2 moles per mole of the compound G. Thereaction temperature is 0 to 50° C., preferably room temperature. Thereaction time is preferably 5 to 8 hours.

Subsequently, the resulting oxime of the compound G is reacted withp-toluenesulfonyl chloride in a suitable solvent in the presence of abase to obtain a p-tosylic acid ester of the compound G. Silica gel isadded to the ester in the same solvent, followed by a Beckmannrearrangement reaction to obtain a mixture of compound Ha and compoundHb. The solvent to be used is not limited specifically insofar as itdoes not participate in the reaction. Examples of such solvents arebenzene, toluene, xylene and like aromatic hydrocarbons, chloroform,dichloromethane, dichloroethane and like hydrocarbon halides. Examplesof useful bases are trimethylamine, trimethylamine, pyridine and liketertiary amines. For the reaction, the base and p-toluenesulfonicchloride are used each in 2 to 3 moles per mole of the oxime of thecompound G. The reaction temperature for tosylation is about 0 to 10°C., and the reaction time is about 4 to about 8 hours. The beckmannrearrangement reaction in silica gel is conducted at a temperature ofabout 10 to about 30° C. for about 12 to about 24 hours.

(Step vii-b) The resulting mixture of compound Ha and compound Hb isreacted with a compound 5 in a suitable solvent in the presence of abase to obtain a compound 4a and compound 4b. The solvent is not limitedspecifically insofar as it does not participate in the reaction.Examples of useful solvents are benzene, toluene, xylene and likearomatic hydrocarbons, chloroform, dichloromethane, dichloroethane andlike hydrocarbon halides. Examples of useful bases are tertiary aminessuch as trimethylamine, triethylamine and pyridine. For the reaction,compound 5 and the base are used each in about 1 to about 2 moles permole of the mixture. The reaction temperature is about 0 to about 50°C., preferably about 10° C. to about 35° C. The reaction time is 12 to36 hours, preferably about 24 to about 36 hours. The mixture of compound4a or compound 4b resulting from the reaction can be isolated andpurified by a usual method such as chromatography and the like. Thecompound 4a or compound 4b resulting from the reaction can be used forthe subsequent reaction, as isolated or without being isolated.

(Step, viii) The compound 4a or compound 4b is hydrogenated in asuitable solvent in the presence of a catalyst to obtain a compound 1'aor 1'b. The solvent is not limited specifically insofar as it does notparticipate in the reaction. Examples of useful solvents are methanol,ethanol, propanol, isopropanol and like alcohols, dioxane,1,2-dimethoxyethane, tetrahydrofuran and like ethers, and methylacetate, ethyl acetate and like acetic acid esters. As a catalyst isused for example palladium-charcoal and platinum. For the reaction, thecatalyst is used preferably in the ratio of 0.5 to 1 by weight based onthe compound 4a or 4b. The reaction temperature is preferably aroundroom temperature to about 50° C. The reaction time is about 10 to about20 hours.

(Step ix) The compound 1'a or compound 1'b is acylated in a suitablesolvent by the method disclosed for example in JP-A-106,593/1986 toobtain a compound 1"a or 1"b. The solvent is not limited specificallyinsofar as it does not participate in the reaction. Examples of usefulsolvents are dichloromethane, dichloroethane, chloroform and likehydrocarbon halides, dioxane, tetrahydrofuran and like ethers, benzene,toluene and like aromatic hydrocarbons.

Usual acylation method is employed, and for example acid anhydridemethod and acid chloride method are applicable.

In acid anhydride method, the compound 1'a or compound 1'b is reactedwith acid anhydride in a suitable solvent in the presence or absence ofdimethylaminopyridine. As acid anhydride is used those having acyl groupwhich should be introduced to R^(1a). Examples thereof are aceticanhydride, propionic anhydride, butyric anhydride and benzoic anhydride.For the reaction, acid anhydride is used in about 1 to about 3 moles anddimethylaminopyridine is used in 0 to about 3 moles each per mole of thecompound 1'a or compound 1'b. The reaction temperature is about 5 toabout 50° C., preferably about 10° C. to around room temperature. Thereaction time is 4 to 24 hours, preferably about 6 to about 12 hours.

In acid chloride method, the compound 1'a or compound 1'b is reactedwith acyl halide (R^(1a) X) in a suitable solvent in the presence adehydrohalogenation agent. Examples of dehydrohalogenation agents aresodium hydrogen carbonate, sodium carbonate, potassium carbonate,pyridine and triethylamine. The solvent includes those mentioned above.For the reaction, acyl halide is used in about 1 to about 3 moles permole of the compound 1'a or compound 1'b. The reaction temperature isabout -30 to about 100° C., preferably around room temperature to 80° C.The reaction time is 1 to 20 hours, preferably about 6 to about 12hours.

Further, the bicyclolactam compound of the present invention wherein Ris oxo group can be prepared, for example, by the following reactionprocess. ##STR29## wherein Q, R², l and X are as defined above.

According to the above reaction step (vii-b), the compound 6 is reactedwith the compound 5 in a suitable solvent in the presence of a base toobtain a compound 1'". The solvent is not limited specifically insofaras it does not participate in the reaction. Examples of such solventsare benzene, toluene, xylene and like aromatic hydrocarbons,dichloromethane, dichloroethane and like hydrocarbon halides. Examplesof useful bases are potassium carbonate, sodium carbonate and likeinorganic bases, sodium methoxide, sodium ethoxide and like sodiumalkoxides, trimethylamine, triethylamine, pyridine and like tertiaryamines. For the reaction, the compound 5 and the base are used each in 1to 2 moles per mole of the compound 6. The reaction temperature is about0 to 50° C., preferably 10 to 35° C., and the reaction time is 1 to 24hours, preferably about 6 to about 12 hours.

The compound 6 can be prepared by the following A, B or C process.

A process: ##STR30##

The compound I is obtained by cyclizing2-cyanoethyl-1,3-cyclohexanedione according to the method disclosed inJ. Org. Chem., 57, 2521 (1992). The compound I is reduced in a suitablesolvent with hydrogen in the presence of palladium-charcoal to obtainthe compound 6a wherein two hydrogen atoms on both of the bridgeheadcarbons have cis configuration. The solvent is not limited specificallyinsofar as it does not participate in the reaction. Examples of usefulsolvents are methanol, ethanol, isopropanol and like alcohols, dioxane,12,-dimethoxyethane, tetrahydrofuran and like ethers. For the reaction,palladium-charcoal is used in the ratio of 0.1 to 1.2 by weight based onthe compound I. The hydrogen pressure is about 1 to 3 atom. The reactiontemperature is 0 to 50° C., preferably 10° C. to around roomtemperature. The reaction time is preferably about 6 to about 12 hours.The resulting compound 6a can be used for the subsequent reaction forobtaining the present compound 1'", as isolated or without beingisolated. ##STR31##

(Step B-i) A known compound J disclosed for example in Synthesis, 176(1991) is reacted in a suitable solvent with methyl ester oracetylenecarboxylic acid to obtain a compound K. The solvent is notlimited specifically insofar as it does not participate in the reaction.Examples of useful solvents are N,N-dimethylformaide,N,N-dimethylacetamide, acetonitrile and like aprotic polar solvents,dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers. Methylester of acetylenecarboxylic acid is used in an excess amount,preferably about 4 to 7 moles per mole of the compound J. The reactiontemperature is preferably about 120 to 150° C., and the reaction time ispreferably about 6 to about 18 hours. The resulting compound K can beused for the subsequent reaction, as isolated or without being isolated.

(Step B-ii) The resulting compound K is reduced in a suitable solventwith hydrogen in the presence of palladium-charcoal to obtain thecompound L. The solvent is not limited specifically insofar as it doesnot participate in the reaction. Examples of useful solvents aremethanol, ethanol, isopropanol and like alcohols, dioxane,1,2-dimethoxyethane, tetrahydrofuran and like ethers. For the reaction,palladium-charcoal is used in the ratio of 0.1 to 0.5 by weight based onthe compound K. The hydrogen pressure is about 1 to 5 atom. The reactiontemperature is 10 to 50° C., preferably 15 to 30° C. The reaction timeis preferably about 2 to about 5 hours. The resulting compound L can beused for the subsequent reaction, as isolated or without being isolated.

(Step B-iii) The resulting compound L is heated without solvent toobtain a compound M. The heating is conducted at a temperature of about170 to about 190° C. and for about 1 to about 3 hours.

Consequently, the compound M is reduced according to the methodmentioned in the above A process to obtain a compound 6b. The resultingcompound 6b can be used for the subsequent reaction for obtaining thepresent compound 1'", as isolated or without being isolated. ##STR32##

(Step C-i) To a known compound N disclosed for example in J. Org. Chem.,31, 1489 (1966) is added an excess amount of 25%-aqueous ammoniasolution or methanol-ammonia for reaction, thereby a compound O isobtained. The reaction temperature is preferably about 15 to about 30°C. The reaction time is preferably about 3 to about 10 hours.

(Step C-ii) The resulting compound O is ring-closed with dehydrationaccording to the method disclosed for example in J. Org. Chem., 35, 3499(1970) to obtain a compound P. The reaction temperature is about 70 toabout 120° C., preferably around a boiling temperature of solvent. Thereaction time is preferably about 2 to about 6 hours.

Consequently, the compound P is reduced according to the methodmentioned in the above A process to obtain a compound 6c. The resultingcompound 6c can be used for the subsequent reaction for obtaining thepresent compound 1'", as isolated or without being isolated.

The compound of the formula (1) thus obtained can be isolated andpurified by a usual method such as recrystallization or columnchromatography. The racemic compound obtained can be divided into thedesired optical isomers, for example, by fractional recrystallizationfor the separation of salts from optically active acids or by passing acolumn packed with an optically active carrier. The stereoisomers can beindividually separated off and purified by a usual method such asfractional crystallization or chromatography.

The present bicyclolactam compound is added to a pharmaceutical carrierto afford a pharmaceutical composition, particularly an anxiolyticagent.

The anxiolytic agent having incorporated the present compound therein asan effective component can be given orally or parenterally to mammalsincluding man. The pharmaceutical preparations of the present inventionare not limited specifically in the unit form of administration but canbe in various forms in conformity with preventive or therapeuticpurposes. These forms of preparations include, for example, oralpreparations, injections, suppositories, external preparations (such aspoultices and like plasters, ointments, creams and lotions), eye drops,nasal drops or sprays, etc.

The anxiolytic agent having incorporated the present compound therein asan effective component is prepared and used in the form of a compositionhaving a desired conventional pharmaceutical carrier or excipeintincorporated therein by a usual method.

Stated more specifically, examples of carriers for use in formulatingthe agent as tablets, encapsulated preparations, granules, powders, etc.for oral administration are excipients such as lactose, sucrose, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose and silicic acid, binders such as water, ethanol, propanol,syrup, glucose solution, starch solution, gelatin solution,carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch,shellac, methyl cellulose, ethyl cellulose, potassium phosphate andpolyvinylpyrrolidone, disintegrators such as dried starch, sodiumalginate, agar powder, laminaria powder, sodium hydrogencarbonate,calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodiumlaurylsulfate, stearic acid monoglyceride, starch and lactose,disintegration suppressants such as sucrose, stearic acid, cacao butterand hydrogenated oils, absorption promotors such as quaternary ammoniumbases and sodium laurylsulfate, humectants such as glycerin and starch,absorbents such as starch, lactose, kaolin, bentonite and colloidalsilicic acid, glazing agents such as purified talc, stearic acid salts,boric acid powder and polyethylene glycol, corrigents such as sucrose,bitter orange peel, citric acid and tartaric acid, etc. When required,the tablets can be those having a usual coating, such as sugar-coatedtablets, gelatin-coated tablets, enteric-coated tablets, film-coatedtablets, double-layer tablets and multi-layer tablets. The encapsulatedpreparation is made by mixing the present compound with carriers such asthose exemplified above and filling the mixture into hard gelatincapsules or soft capsules.

Liquid preparations for oral administration include aqueous or oilysuspensions, solutions, syrups and elixirs, and are prepared in theusual manner by adding a corrigent, buffer, stabilizer, flavoring agent,to the present compound. In this case, examples of useful corrigents arethose exemplified above, useful buffers include sodium citrate, anduseful stabilizers include tragacanth, gum arabic and gelatin, etc.

Injections are aqueous or oily suspensions and solutions, or powderyfillers and freeze-dried preparations which are dissolved when to beused. Injections are prepared in the usual manner by adding to thepresent compound a pH adjusting agent, buffer, stabilizer, isotonicagent, diluent, local anesthetic, etc. Examples of pH adjusting agentsand buffers for use in this case are sodium citrate, sodium acetate,sodium phosphate and the like. Examples of useful stabilizers are sodiumpyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc. Examples ofuseful diluents are water, aqueous solution of lactic acid, ethylalcohol, propylene glycol, ethoxylated isostearyl alcohol,polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid ester,etc. Examples of useful stabilizers are sodium pyrosulfite, EDTA,thioglycolic acid, thiolactic acid, etc. Examples of useful localanesthetics are procaine hydrochloride, lidocaine hydrochloride, etc.

In preparing suppositories, use can be made of carriers such aspolyethylene glycol, lanolin, cacao fat, esters of higher alcohols,gelatin, semisynthetic glyceride, etc., and when required, surfactantssuch as Tween (trademark).

Ointments (pastes, creams, gels, etc.) are prepared by admixing with thepresent compound a base, stabilizer, lubricant, preservative, etc. whichare usually used. Examples of bases are fluid paraffin, whitepetrolatam, bleached beeswax, octyldodecyl alcohol, paraffin and thelike. Examples of useful preservatives are methyl p-hydroxybenzoate,ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like.

Plasters are prepared by applying the ointment, cream, gel, paste or thelike to a usual support in the conventional manner. Examples of suitablesupports are woven or nonwoven fabrics of cotton, staple fiber orchemical fiber, films of flexible polyvinyl chloride, polyethylene,polyurethane or the like, and foamed sheets of such material.

When required, the foregoing preparations may have further incorporatedtherein a coloring agent, preservative, perfume, flavoring, sweetenerand the like, and other medicinals.

The method of administering the pharmaceutical preparation of theinvention is not limited specifically but determined according to theform of preparation, age, sex and other conditions of the patient anddegree of symptom of the patient. For example, tablets, pellets,powders, solutions, suspensions, emulsions, granules and capsules aregiven orally. Suppositories are introduced into the rectum. Injectionsare intravenously given singly or as mixed with a usual auxiliarysolution such as glucose or amino acid solution. Further when required,they are singly administered intra-arterially, intramuscularly,intracutaneously, subcutaneously or intraperitoneally. Ointments areapplied to the skin, mucus membrane of the oral cavity, etc. Plastersare applied to the skin.

The dosage of the effective component of the preparation of theinvention can be suitably determined according to the mode ofadministration, age, sex and other conditions of the patient and degreeof the symptom. Generally the effective component is administered at adaily dose usually of 0.001 to 50 mg/kg body weight, preferably 0.01 to10 mg/kg body weight. The present preparation can be given once or inabout 2 to about four divided doses per day.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention will be described below with reference toreference examples and examples. However, the invention is not limitedby these examples.

REFERENCE EXAMPLE 1 Preparation of6-oxo-bicyclo[3.3.0]octan-2-one=ethylene=acetal (Compound B-1)

A 9.62 g quantity of bicyclo[3.3.0]octan-2,6-dione which is known asdisclosed for example in J. Org. Chem., 42, 3764˜3767 (1977), 0.265 g ofp-toluenesulfonic acid monohydrate and 4.54 g of ethylene glycol weredissolved in 50 ml of benzene, and the mixture was refluxed for reactionfor 6 hours while removing water as an azeotropic mixture. After thereaction, the mixture was cooled to room temperature and allowed tostand for 15 minutes with addition of 3 g of sodium hydrogencarbonate.The resulting precipitate was filtered off and washed with benzene. Thefiltrate was concentrated to obtain a brown oily product, which waspurified by column chromatography using 180 g of silica gel andhexane-ethyl acetate (5:1) to obtain 9.28 g of Compound mentioned abovein the form of a colorless oily substance (yield: 73%).

¹ H-NMR (CDCl₃) δ ppm: 1.80˜2.45 (m, 10H), 3.95 (s, 4H)

REFERENCE EXAMPLE 2 Preparation of (1RS, 2SR,5RS)-2-hydroxybicyclo-[3.3.0]octan-6-one=ethylene=acetal (Compoundtrans-C-1)

A 9.23 g quantity of Compound obtained in Reference Example 1 wasdissolved in 70 ml of methanol, and 1.93 g of sodium-boron hydride wasadded to the solution while cooling the solution in an ice-methanolbath. The mixture was returned to room temperature 30 minutes later,followed by further reaction for 1 hour. The methanol was thereafterdistilled off, 70 ml of water was added to the residue, and the mixturewas subjected to extraction with 100 ml of dichloromethane and 50 ml ofdichloromethane twice. The dichloromethane layer obtained was washedwith 50 ml of saturated aqueous sodium chloride solution, then driedover anhydrous sodium sulfate and distilled for the removal of solvent,giving a colorless oily product. The product was purified by columnchromatography using 150 g of silica gel and hexane-ethyl acetate (4:1to 2:1) to obtain 6.63 g of Compound mentioned above in the form of acolorless oily substance (yield: 71%).

¹ H-NMR (CDCl₃) δ ppm: 1.75˜2.00(m, 8H), 2.10˜2.80(m, 2H), 3.90˜4.18 (m,1H), 3.94(s, 4H)

REFERENCE EXAMPLE 3 Preparation of (1RS, 2RS,5RS)-2-(4-nitrobenzoyl-oxy)bicyclo-[3.3.0]octan-6-one=ethylene=acetal(Compound D-1)

A 3.68 g quantity of Compound obtained in Reference Example 2, 6.68 g ofp-nitrobenzoic acid and 10.5 g of triphenylphosphine were dissolved in70 ml of tetrahydrofuran, and a solution of 7.00 g of diethylazodicarboxylate in 10 ml of tetrahydrofuran was added dropwise to thesolution with ice cooling over a period of 10 minutes. The mixture wasstirred with ice cooling for 1 hour, then returned to room temperatureand further reacted for 16 hours. The solvent was distilled off from thereaction mixture, 50 ml of ether and 30 ml of hexane were added to theresidue, and the resulting mixture was allowed to stand in arefrigerator for 1 day. The resulting precipitate (triphenylphosphineoxide) was filtered off and washed with hexane-ether (2:1). The filtrateobtained was concentrated to obtain a yellow oily product. The productwas purified by column chromatography using 90 g of silica gel, hexaneand hexane-ethyl acetate (10:1), giving 5.34 g of Compound mentionedabove in the form of a light yellow oily substance (yield: 80%).

¹ H-NMR (CDCl₃) δ ppm: 1.60˜2.20(m, 8H), 2.45˜2.90(m, 2H), 3.94(s, 4H),5.10˜5.23(m, 1H), 8.24(s, 4H)

REFERENCE EXAMPLE 4 Preparation of (1RS, 2RS,5RS)-2-hydroxybicyclo-[3.3.0]octan-6-one=ethylene=acetal (Compoundcis-C-1)

A 12.85 g quantity of Compound obtained in Reference Example 3 wasdissolved in 100 ml of methanol, 15 g of an anion exchange resin,Amberlite IR400 (OH⁻) (product of Organo Co., Ltd.), was added to thesolution, and the mixture was refluxed for 8 hours. Since the startingmaterial still remained, 10 g of the anion exchange resin was furtheradded to the mixture, followed by refluxing for 16 hours. The reactionmixture was returned to room temperature, filtered through High FlowSupercell (product of Nacalai Tesque Co., Ltd.) and washed withmethanol. The resulting filtrate was concentrated and purified by columnchromatography using 100 g of silica gel and hexane-ethyl acetate (3:1),whereby 6.52 g of Compound above-mentioned was obtained as a colorlessoily substance (yiled: 92%).

¹ H-NMR (CDCl₃) δ ppm: 1.20˜2.15(m, 8H), 2.30˜2.80(m, 2H), 3.80˜4.10(m,1H), 3.91(s, 4H)

REFERENCE EXAMPLE 5 Preparation of (1RS, 2RS,5RS)-2-benzyloxybicyclo-[3.3.0]-octan-6-one-=ethylene=acetal (CompoundF-1)

A 6.40 g quantity of Compound obtained in Reference Example 4 wasdissolved in 40 ml of N,N-dimethylformamide, 2.08 g of 60% sodiumhydride was added to the solution, and the mixture was stirred at roomtemperature. The reaction temperature rose to about 45° C. withevolution of hydrogen. One hour later, the reaction mixture was cooledwith ice, followed by addition of 6.3 ml of benzyl bromide. The mixturewas returned to room temperature 30 minutes thereafter and stirred for24 hours, followed by further reaction on a bath of 70° C. for 4 hours.The mixture was returned to room temperature, and 80 ml of ice water wasadded thereto. The resulting mixture was subjected to extraction with 60ml of ether three times. The ethereal layer was washed with 20 ml ofwater three times and with 20 ml of saturated aqueous solution of sodiumchloride and thereafter dried over anhydrous sodium sulfate. Removal ofthe solvent from the layer gave an oily product, which was then purifiedby column chromatography using 75 g of silica gel and hexane andhexane-ether (15:1), whereby 6.65 g of Compound mentioned above wasobtained as an oily substance (yield: 70%).

¹ H-NMR (CDCl₃) δ ppm: 1.60˜2.10(m, 8H), 2.40˜2.80(m, 2H), 3.50˜3.80(m,1H), 3.90(s, 4H), 4.92(s, 2H), 7.31(s, 5H)

REFERENCE EXAMPLE 6 Preparation of (1RS, 2RS,5RS)-2-benzyloxybicyclo-[3.3.0]-octan-6-one (Compound G-1)

A 1.94 g quantity of Compound obtained in Reference Example 5 wasdissolved in 10 ml of tetrahydrofuran, and the solution was stirred for6 hours with 3 ml of 2N hydrochloric acid added thereto. Thetetrahydrofuran was distilled off from the resulting reaction mixture,followed by extraction with 20 ml of ether twice. The ethereal layer waswashed with 10 ml of saturated aqueous solution of sodiumhydrogencarbonate twice and then with 5 ml of saturated aqueous solutionof sodium chloride, and dried over anhydrous sodium sulfate. Removal ofthe solvent from the layer give 1.60 g of Compound mentioned above as anoily substance (yield: 98%).

¹ H-NMR (CDCl₃) δ ppm: 1.30˜2.40(m, 8H), 2.60˜3.00(m, 2H), 3.70˜3.90(m,1H), 4.51(s, 2H), 7.33(s, 5H)

REFERENCE EXAMPLE 7 Preparation ofcis-2-azabicyclo[4.4.0]decan-3,7-dione (Compound 6a)

Methanol (100 ml) was added to 1.5 g of2,3,4,5,6,7,8-heptahydro-1(1H)-quinoline-2,5-dione which was known asdisclosed for example in J. Org. Chem., 57, 2522 (1992). The mixture wassubjected to reduction in the hydrogen stream (1 atm.) in the presenceof 0.75 g of 10% palladium-carbon. The palladium-carbon was filtered offand the solvent was removed. The residue was purified for isolation bycolumn chromatography (silica gel, developer; chloroform; ethanol=10:1)to obtain 0.42 g of Compound mentioned above (yield: 28%). Table 1 showsanalytical data.

REFERENCE EXAMPLE 8 Preparation of methyl3-(3-amino-2-cyclopenten-1-one-2-yl)-acrylate (Compound K)

To 2 ml of dimethylacetamide were added 0.2 g of3-amino-2-cyclopenten-1-one and 2 ml of methyl acetylenecarbonate. Themixture was heated with stirring at 120 to 125° C. for 19 hours. Aftercooled, 2 ml of ether was added and the precipitates were filtered andwashed with ether to obtain 0.17 g of Compound mentioned above (yield:46%). m.p. 278˜279 °C.

Elementary analysis; C₉ H₁₁ NO₃ ; Calcd. C, 59.67; H, 6.12; N, 7.73;Found C, 59.34; H, 6.47; N, 8.06.

REFERENCE EXAMPLE 9 Preparation of methyl3-(3-amino-2-cyclopenten-1-one-2-yl)-propionate (Compound L)

To 200 ml of methanol were added 6.0 g of Compound K obtained inReference Example 8 and 1.5 g of 10% palladium-charcoal. The mixture wasreacted at room temperature in the hydrogen stream (2 atm.) for 3 hours.After reaction, the palladium-carbon was filtered off and the solventwas removed. The residue was crystallized from ether to obtain 5.9 g ofCompound mentioned above (yield: 98%).

m.p. 223˜224° C.

Elementary analysis; C₈ H₁₁ NO₃.0.2 H₂ O; Calcd. C, 55.61; H, 6.65; N,8.11; Found C, 55.58; H, 6.69; N, 8.31.

REFERENCE EXAMPLE 10 Preparation of2,3,4,5,6,7-hexahydro-1(1H)-pyrindin-2,5-dione (Compound M)

A 2.8 g quantity of Compound L obtained in Reference Example 9 washeated with stirring without solvent at an oil bath temperature of 190to 210° C. for one hour. After reaction, when hot, isopropanol wasadded. After cooling, the precipitates were filtered to obtain 1.7 g ofCompound mentioned above (yield: 74%).

m.p. 247˜248° C.

Elementary analysis; C₈ H₉ NO₂ ; Calcd. C, 63.56; H, 6.00; N, 9.27;Found C, 63.25; H, 6.17; N, 9.30.

REFERENCE EXAMPLE 11 Preparation ofcis-2-azabicyclo[4.3.0]nonan-3,7-dione (Compound 6b)

In 180 ml of methanol was suspended 3.8 g of Compound N obtained inReference Example 10 and thereto was added 4 g of 10%palladium-charcoal. The mixture was reacted in the hydrogen stream (2 to2.5 atm.) for 12 hours. After reaction, the palladium-charcoal wasfiltered off and the filtrate was concentrated. The residue was purifiedby column chromatography (silica gel, developer; ethyl acetate:methanol=10:1) to obtain 3.4 g of Compound mentioned above (yield: 89%).Table 1 shows analytical data.

REFERENCE EXAMPLE 12 Preparation of2-methyl-2-(2-carbamoylethyl)-1,3-cyclopentanedione (Compound 0-1)

A 1 ml quantity of 25% aqueous ammonia solution was added to 1.6 g of2-methyl-2-(β-carbomethoxyethyl)-cyclopentan-1,3-dione which was knownand disclosed for example in J. Org. Chem., 31, 1489 (1966). The mixturewas reacted at room temperature for 5 hours. After reaction, 10 ml oftetrahydrofuran (THF) was added. The insolubles were filtered andrecrystallized from ethanol to obtain 0.6 g of Compound mentioned above(yield: 41%).

m.p. 159˜162° C.

REFERENCE EXAMPLE 13 Preparation of2,3,4,4a,5,6-hexahydro-4a-methyl-1(1H)-pyrindin-2,5-dione (Compound P-1)

To 400 ml of toluene was added 4.42 g of Compound 0-1 obtained inReference Example 12, and thereto was added 0.6 g of tosyl acid. Themixture was heated with stirring for 3 hours with dehydration deviceattached. After reaction, the solvent was removed and the residue wasrecrystallized from ethanol-chloroform to obtain 3.0 g of Compoundmentioned above (yield: 75%).

m.p. 228˜230° C.

Elementary analysis; C₉ H₁₁ NO₂ ; Calcd. C, 65.44; H, 6.71; N, 8.30;Found C, 65.13; H, 6.67; N, 8.30.

REFERENCE EXAMPLE 14 Preparation ofcis-6-methyl-2-azabicyclo[4.3.0]-nonan-3,7-dione (Compound 6c-1)

Compound mentioned above was prepared in the same manner as in ReferenceExample 11 except that Compound P-1 obtained in Reference Example 13 wasused in place of Compound M. Table 1 shows analytical data.

                                      TABLE 1                                     __________________________________________________________________________     ##STR33##              (Compound 6)                                                                  elem. anal.                                           Compd     yield                                                                            m.p.       calcd. (found)                                                                           MS                                         No. Q  1  (%)                                                                              (° C.)                                                                      formula                                                                             C   H   N  (M.sup.+)                                  __________________________________________________________________________    6a  H  2  28 177˜178                                                                      C.sub.9 H.sub.13 NO.sub.2                                                           64.65                                                                             7.84                                                                              8.38                                                                             167                                                                (64.65                                                                            7.37                                                                              8.34)                                         6b  H  1  71 140˜142                                                                      C.sub.8 H.sub.11 NO.sub.2.                                                          60.59                                                                             7.37                                                                              8.83                                                                             153                                                          0.3 H.sub.2 O                                                                       (60.41                                                                            7.08                                                                              8.88)                                         6c-1                                                                              CH.sub.3                                                                         1  77 129˜131                                                                      C.sub.9 H.sub.13 NO.sub.2                                                           64.65                                                                             7.84                                                                              8.38                                                                             167                                                                (64.41                                                                            7.58                                                                              8.32)                                         __________________________________________________________________________

EXAMPLE 1 Preparation of (1RS, 6RS,7RS)-7-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3-one(Compound 4a-1) and (1RS, 6RS,7RS)-7-benzyloxy-3-(4-methoxybenzoyl)-3-azabicyclo[4.3.0]nonan-2-one(Compound 4b-1)

A 1.54 g quantity of Compound obtained in Reference Example 6 wasdissolved in 15 ml of tetrahydrofuran, followed by addition of 8 ml ofwater and thereafter by addition of 0.94 g of hydroxylaminehydrochloride and 1.84 g of sodium acetate trihydrate. Tetrahydrofuranwas subsequently added to obtain a homogeneous mixture, which was thenstirred at room temperature for 5 hours. The tetrahydrofuran wasdistilled off from the reaction mixture, followed by extraction with 80ml of ethyl acetate. The ethyl acetate layer was washed with 10 ml ofwater, with 10 ml of saturated sodium hydrogencarbonate solution andsubsequently with 10 ml of saturated aqueous solution of sodiumchloride, and thereafter dried over anhydrous sodium sulfate.Distillation of the layer for the removal of the solvent gave 1.64 g ofoxime of Compound of Reference Example 6 as a colorless oily substance.

A 1.60 g of the oxime obtained was dissolved in 16 ml of benzene,followed by addition of 3.11 g of p-toluenesulfonyl chloride and then byaddition of 2.27 ml of triethylamine was ice cooling. The mixture wasstirred for 4 hours with ice cooling and subsequently for 2 hours atroom temperature, and thereafter diluted with 50 ml of ether. Theresulting solution was washed with 10 ml of water, with 10 ml of 2Nhydrochloric acid twice and subsequently with 10 ml of saturated aqueoussolution of sodium chloride, and thereafter dried over anhydrous sodiumsulfate. Removal of the solvent from the solution gave a yellow oilyproduct. The product was dissolved in 50 ml of anhydrous benzene,followed by addition of 43 g of silica gel (Fuji Silysia, BW-300 aswashed with 2N HCl and then thoroughly with water, and dried at 230° C.for 16 hours) and further by addition of anhydrous benzene in an amountof permitting stirring of the resulting mixture. The mixture was shakenon a water bath having a constant temperature of 25° C. for 18 hours.The reaction mixture was poured into a column packed with 20 g of silicagel, and 300 ml of benzene was passed through the column to cause anexcess of p-toluenesulfonyl chloride to flow out. The solvent wasthereafter changed for benzene-methanol (6:1) to obtain an eluate. Theeluate still contained impurities and was therefore purified by columnchromatography again using 30 g of silica gel, and chloroform andchloroform-methanol (50:1). the product was dried in a vacuum at roomtemperature to obtain 1.233 g of a light yellow oily substance. ¹ H-NMRanalysis revealed that the product was a mixture of (1RS, 6RS,7RS)-7-benzyloxy-2-azabicyclo[4.3.0]nonan-3-one and (1RS, 6RS,7RS)-7-benzyloxy-3-azabicyclo[4.3.0]nonan-2-one approximately in theratio of 2:1.

The mixture (1.18 g) obtained was dissolved in 15 ml of dichloromethane,1.31 g of p-methoxybenzoyl chloride and 1.34 g of triethylamine wereadded to the solution, and the mixture was stirred at room temperaturefor 36 hours. With addition of 80 ml of ethyl acetate, the reactionmixture was washed with 20 ml of 2N hydrochloric acid twice, with 20 mlof saturated solution of sodium hydrogencarbonate twice and then with 10ml of saturated aqueous solution of sodium chloride, and dried overanhydrous sodium sulfate. Removal of the solvent gave a brown oilyproduct, which was then purified by column chromatography using 30 g ofsilica gel and hexane-ethyl acetate (4:1 to 3:1). The component elutedfirst was Compound 4b-1 mentioned above and obtained in an amount of0.576 g as a yellow oily substance (yield: 25%). The component elutedthereafter was Compound 4a-1 mentioned above. The fraction was distilledfor the removal of the solvent and recrystallized from ethanol, giving1.05 g of the compound (yield: 46%). Tables 2 to 3 show analytical data.

EXAMPLE 2

Compounds 4a-2 to 4a-5 and Compounds 4b-2 to 4b-4 were prepared in thesame manner as in Example 1 except that various benzoic chloridederivatives were used in place of p-methoxybenzoic chloride. Tables 2 to3 show analytical data.

EXAMPLE 3 Preparation of (1RS, 6RS,7RS)-7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo-[4.3.0]nonan-3-one(Compound 1'a-1)

A 1.05 g quantity of (1RS, 6RS,7RS)-7-benzyloxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3-one(Compound 4a-1) obtained in Example 1 was dissolved in 15 ml of dioxane,0.50 g of 10% palladium-charcoal (product of Wako Junyaku Co., Ltd.) wasadded to the solution, and the air in the reactor was removed by anaspirator and replaced by hydrogen repeatedly twice. The mixture wasthereafter stirred in the hydrogen atmosphere (1 atm.) for 16 hours. Thecatalyst was filtered off and washed with dioxane. The resultingfiltrate was concentrated to obtain a colorless oily product, which wasthen purified by column chromatography using 15 g of silica gel andchloroform. Removal of the solvent from the product afforded crystals,which were further recrystallized from ether, giving 0.64 g of Compoundmentioned above in the form of a colorless powder (yield: 81%). Table 4shows analytical data.

EXAMPLE 4

Compounds 1'a-2 to 1'a-5 were prepared in the same manner as in Example3 except that Compounds 4a-2 to 4a-5 obtained in Example 2 were used asa starting material in place of Compound 4a-1. Similarly, Compounds1'b-2 and 1'b-3 were prepared in the same manner as in Example 3 exceptthat Compounds 4b-3 and 4b-4 obtained in Example 2 were used as astarting material in place of Compound 4b-1. Tables 4 to 5 show yieldand analytical data.

EXAMPLE 5

Preparation of (1RS, 6RS,7RS)-7-acetoxy-2-(4-methoxybenzoyl)2-azabicyclo-[4.3.0]nonan-3-one(Compound 1"a-1) A 0.29 g quantity of (1RS, 6RS,7RS)-7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonan-3-one(Compound 1'a-1) obtained in Example 3 was dissolved in 10 ml ofdichloromethane. With ice cooling, thereto were added 0.225 g ofdimethylaminopyridine and then 0.2 g of acetic anhydride. The mixturewas reacted at room temperature for 12 hours and then thereto was added20 ml of dichloromethane. The reaction mixture was washed with 10 ml of1N-hydrochloric acid and then with 10 ml of saturated aqueous solutionof sodium chloride, and dried over anhydrous sodium sulfate. Removal ofthe solvent gave a light brown oily product, which was then purified bycolumn chromatography using 20 g of silica gel and chloroform-methanol(20:1) to obtain 0.23 g of Compound 1"a-1 as an oily substance (yield:69%).

¹ H-NMR (CDCl₃) δ ppm: 1.60˜2.70(m, 9H), 2.08(s, 3H), 3.85(s, 3H),4.70(q, 1H), 5.00˜5.10(m, 1H), 6.88(d, 2H), 7.10(d, 2H)

                  TABLE 2                                                         ______________________________________                                         ##STR34##                                                                    Com-                                                                          pd.            yield  m.p.   .sup.1 H-NMR(CDCl.sub.3)                         No.  (R.sup.5)n                                                                              (%)    (° C.)                                                                        (δ ppm)                                    ______________________________________                                        4a-1 4-OCH.sub.3                                                                             46     108.5  1.30˜2.70(m, 10H),                                               ˜                                                                              3.70˜4.00(m, 1H),                                                109.5  3.83(s, 3H), 4.54(s, 2H),                                                     6.87(d, 2H), 7.34(s, 5H),                                                     7.58(d, 2H)                                      4a-2 H         26     oil    1.50˜2.31(m, 6H),                                                       2.40˜2.57(m, 3H),                                                       3.89(m, 1H), 4.52(m, 2H),                                                     4.55(q, 1H), 7.26˜7.58(m, 10H)             4a-3 4-F       27     oil    1.10˜2.25(m, 6H),                                                       2.25˜2.75(m, 3H),                                                       3.70˜3.95(m, 1H), 4.55(dd, 2H),                                         4.70(q, 1H), 6.90˜7.70(m, 9H),             4a-4 4-CH.sub.3                                                                              28     97˜98                                                                          1.00˜2.30(m, 6H), 2.36(s, 3H),                                          2.30˜2.70(m, 3H),                                                       3.70˜4.00(m, 1H),                                                       4.54(dd, 2H), 4.69(q, 1H),                                                    7.10˜7.60(m, 9H)                           4a-5 2,4-(OCH.sub.3).sub.2                                                                   20     oil    1.42˜2.06(m, 5H),                                                       2.25˜2.50(m, 4H),                                                       3.73(s, 3H), 3.79(s, 3H),                                                     3.86(m, 1H), 4.50(d, 1H),                                                     4.53(d, 1H), 4.58(q, 1H),                                                     6.50(d, 1H), 6.54(dd, 1H),                                                    7.28(m, 1H), 7.32(d, 1H),                                                     7.35(m, 4H)                                      ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR35##                                                                    Com-                                                                          pd            yield  m.p. .sup.1 H-NMR(CDCl.sub.3)                            No.  (R.sup.5)n                                                                             (%)    (° C.)                                                                      (δ ppm)                                       ______________________________________                                        4b-1 4-OCH.sub.3                                                                            25     oil  1.30˜3.30(m, 10H), 3.60˜4.10(m,                                   1H),                                                                          3.83(s, 3H), 4.52(s, 2H),                                                     6.86(d, 2H), 7.33(s, 5H), 7.54(d, 2H)               4b-2 4-F      14     128  1.20˜2.30(m, 6H), 2.40˜2.80(m,                                    1H),                                                                     ˜                                                                            2.90˜3.30(m, 1H), 3.40˜3.65(m,                                    1H),                                                                     130  3.65˜3.85(m, 1H), 3.95˜4.25(m,                                    1H),                                                                          4.52(dd, 2H), 6.90˜7.70(m, 9H)                4b-3 4-CH.sub.3                                                                             14     oil  1.20˜2.30(m, 6H), 2.36(s, 3H)                                           2.40˜2.80(m, 1H), 2.90˜3.30(m,                                    1H),                                                                          3.40˜3.65(m, 1H), 3.65˜3.85(m,                                    1H),                                                                          3.95˜4.25(m, 1H), 4.52(dd, 2H),                                         7.10˜7.50(m 9H)                               4b-4 2,4-     17     oil  1.44˜2.52(m, 7H), 3.02(m, 1H),                     (OCH.sub.3).sub.2    3.48(m, 1H), 3.69(s, 3H),                                                     3.71(m, 1H), 3.79(s, 3H),                                                     4.01(m, 1H), 4.48(d, 1H),                                                     4.50(d, 1H), 6.49(d, 1H),                                                     6.52(dd, 1H), 7.22(d, 1H),                                                    7.28(m, 1H), 7.32˜7.38(m,                     ______________________________________                                                                  4H)                                             

                  TABLE 4                                                         ______________________________________                                         ##STR36##                                                                    Com-                                                                          pd            yield  m.p. .sup.1 H-NMR(CDCl.sub.3)                            No.  (R.sup.5)n                                                                             (%)    (° C.)                                                                      (δ ppm)                                       ______________________________________                                        1'a-1                                                                              4-OCH.sub.3                                                                            81     120  1.20˜2.70(m, 10H), 3.84(s, 3H),                                    ˜                                                                            3.90˜4.30(m, 1H), 4.20(q, 1H),                                     121  6.88(d, 2H), 7.59(d, 2H)                            1'a-2                                                                              H        37     137.5                                                                              1.36˜2.29(m, 7H), 2.45(t, 2H),                                     ˜                                                                            3.96(q, 1H), 4.56(q, 1H),                                                139  4.86(d, 1H), 7.41(m, 2H),                                                     7.48˜7.56(m, 3H)                              1'a-3                                                                              4-F      39     110  1.20˜2.80(m, 9H),                                                  ˜                                                                            3.90˜4.25(m, 1H), 4.73(q, 1H),                                     112  6.58˜7.70(m, 4H)                              1'a-4                                                                              4-CH.sub.3                                                                             27     131  1.20˜2.70(m, 9H), 2.37(s, 3H),                                     ˜                                                                            4.00˜4.25(m, 1H), 4.71(q, 1H),                                     133  7.10˜7.60(m, 4H)                              1'a-5                                                                              2,4-     56     114  1.28˜2.27(m, 7H), 2.39(t, 2H),                     (OCH.sub.3).sub.2                                                                             ˜                                                                            3.73(s, 3H), 3.80(s, 3H),                                                115.5                                                                              3.93(m, 1H), 4.59(q, 1H),                                                     4.84(d, 1H), 6.49(d, 1H),                                                     6.54(dd, 1H), 7.31(d, 1H)                           ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                         ##STR37##                                                                    Com-                                                                          pd            yield  m.p. .sup.1 H-NMR(CDCl.sub.3)                            No.  (R.sup.5)n                                                                             (%)    (° C.)                                                                      (δ ppm)                                       ______________________________________                                        1'b-1                                                                              4-OCH.sub.3                                                                            72     108  1.50˜1.70(m, 2H), 1.90˜2.40(m,                                    7H),                                                                     ˜                                                                            3.00˜3.15(m, 1H), 3.50˜3.65(m,                                    1H),                                                                     109  3.80(s, 3H), 3.90˜4.10(m, 1H),                                          6.90(d, 2H), 7.55(d, 2H)                            1'b-2                                                                              4-F      30     oil  1.20˜2.55(m, 7H), 2.95˜3.30(m,                                    1H),                                                                          3.40˜3.80(m, 2H), 3.90˜4.30(m,                                    2H),                                                                          6.90˜7.70(m, 4H)                              1'b-3                                                                              4-CH.sub.3                                                                             28     104  1.30˜2.60(m, 7H), 2.37(s, 3H),                                     ˜                                                                            2.90˜3.30(m, 1H), 3.30˜3.80(m,                                    1H),                                                                     106  3.90˜4.30(m, 2H), 7.10˜7.65(m,          ______________________________________                                                                  4H)                                             

EXAMPLE 6 Preparation ofcis-2-(p-toluoyl)-2-azabicyclo-[4.3.0]nonan-3,7-dione (Compound 1'"-2)

In 20 ml of dichloromethane were dissolved 0.3 g of Compound 6b obtainedin Example 11 and 0.39 g of 4-methylbenzoyl chloride. Thereto was addeddropwise 0.38 ml of triethylamine with ice cooling. The mixture wasreacted at room temperature for 12 hours. The reaction mixture waswashed with 0.1N hydrochloric acid, with 0.1N aqueous solution of NaOHand then with water, and dried over anhydrous sodium sulfate. Afterdried, the solvent was removed and the residue was recrystallized toobtain 0.35 g of Compound mentioned above (yield: 66%). Table 6 showsanalytical data.

EXAMPLE 7

Compound 1'"-1, and Compounds 1'"-3 to 1'"-11 were prepared in the samemanner as in Example 6. Table 6 shows analytical data. Analytical dataof NMR of Compounds 1'"-3 and 1'"-4 were shown below.

Compound 1'"-3

¹ H-NMR(CDCl₃) δ ppm

1.80˜2.90(m, 9H), 3.75(s, 3H), 3.94˜4.20(m, 1H), 6.70˜7.04(m, 2H),7.22˜7.48(m, 2H)

Compound 1'"-4

¹ H-NMR(CDCl₃) δ ppm

1.70˜2.80(m, 9H), 3.80(s, 3H), 4.84˜5.10(m, 1H), 6.90˜7.35(m, 4H)

                  TABLE 6                                                         ______________________________________                                         ##STR38##                                                                    Compound No.                                                                           Q      1      (R.sup.5)n                                                                             yield (%)                                                                            m.p. (° C.)                     ______________________________________                                        1'''-1   H      2      4-OCH.sub.3                                                                            83     169˜171                          1'''-2   H      1      4-CH.sub.3                                                                             66     148˜149                          1'''-3   H      1      2-OCH.sub.3                                                                            85     oil                                    1'''-4   H      1      3-OCH.sub.3                                                                            89     oil                                    1'''-5   H      1      4-OCH.sub.3                                                                            49     115˜117                          1'''-6   H      1      2,4-(OCH.sub.3).sub.2                                                                  74     153˜154                          1'''-7   H      1      2,6-(OCH.sub.3).sub.2                                                                  68     144˜145                          1'''-8   H      1      3.4-(OCH.sub.3).sub.2                                                                  56     123˜125                          1'''-9   H      1      3,5-(OCH.sub.3).sub.2                                                                  81     135˜136                          1'''-10  H      1      3,4,5-(OCH.sub.3).sub.2                                                                79     150˜151                          1'''-11  CH.sub.3                                                                             1      4-OCH.sub.3                                                                            62     111˜113                          ______________________________________                                    

PREPARATION EXAMPLE 1

    ______________________________________                                        Tablet                                                                        ______________________________________                                        Compound 1'a-1          30 mg                                                 Microcrystalline cellulose                                                                            50 mg                                                 Hydroxypropyl cellulose 20 mg                                                 Lactose                 47 mg                                                 Talc                    2 mg                                                  Magnesium stearate      1 mg                                                  ______________________________________                                    

By the usual method, the above ingredients in the proportions given weremade into tablets each weighing 150 mg.

Preparation Example 2

    ______________________________________                                        Granule                                                                       ______________________________________                                        Compound 1'a-5           10 mg                                                Lactose                  400 mg                                               Corn starch              370 mg                                               Hydroxypropylmethyl cellulose                                                                          20 mg                                                ______________________________________                                    

The above ingredients in the proportions given were made into a granularpreparation by the usual method in an amount of 800 mg per wrapper.

Preparation Example 3

    ______________________________________                                        Capsule                                                                       ______________________________________                                        Compound 1'b-1          55 mg                                                 Lactose                 50 mg                                                 Corn starch             50 mg                                                 Microcrystalline cellulose                                                                            94 mg                                                 Magnesium stearate      1 mg                                                  ______________________________________                                    

By the usual method, the above ingredients in the proportions given weremade into a granular preparation in an amount of 250 mg in each capsule.

Preparation Example 4

    ______________________________________                                        Injection                                                                     ______________________________________                                        Compound 1'''-8       10 mg                                                   Sodium chloride       3.5 mg                                                  Distilled water for injections,                                                                     suitable amount                                         ______________________________________                                    

The above ingredients in the proportions given were made into aninjection by the usual method.

Preparation Example 5

    ______________________________________                                        Syrup                                                                         ______________________________________                                        Compound 1'''-9       50 mg                                                   Purified sucrose      60 g                                                    Ethyl para-hydroxybenzoate                                                                          5 mg                                                    Butyl para-hydroxybenzoate                                                                          5 mg                                                    Perfume               suitable amount                                         Coloring agent        suitable amount                                         Purified water        suitable amount                                         ______________________________________                                    

The above ingredients in the proportions given were made into a syrup bythe usual method.

Preparation Example 6

    ______________________________________                                        Suppositories                                                                 ______________________________________                                        Compound 1'''-10      50 mg                                                   Witepsol W-35         1400 mg                                                 ______________________________________                                         (Trademark, a mixture of mono, di and triglyceride of saturated fatty         acids from lauric acid to stearic acid, Dynamite Nobel Co., Ltd.)        

By the usual method, the above ingredients in the proportions given weremade into suppositories.

Test examples are shown below in which 2-azabicyclo[3.4.0]nonane-2-onedisclosed in International Public Disclosure No. WO 91/11434 was used asa comparison compound.

Test Example 1 Anticonflict Test

1. Experimental animals

Wister rats (males weighing 140 to 160 g) were used for experiment ingroups of 11 of 14.

2. Test agents and administration method

Compound 1'a-1, 1'a-5, 1'b-1, 1'"-8, 1'"-9, the above comparisoncompound, diazepam or buspirone was suspended in a 0.5% sodiumcarboxymethyl cellulose solution, and the suspension was orally given tothe animal in a volume of 5 ml/kg one hour before the start ofexperiment.

3. Experimental method and result

With reference to a method described in "Process in Anxiolytics andAntidepressants," edited by Showa Ueki and Tatsuo Furukawa, IshiyakuShuppansha, 56˜59 (1981), the agents were tested using experimentalboxes having a grid floor and a metal drinking tube in the floor. Nowater was supplied to the rats for 48 hours before the experiment. Uponlapse of first 24 hours, each group of rats were placed into theexperimental box, permitted access to water for 30 seconds and caused torecognize the metal drinking tube. Upon lapse of further 24 hours withaccess to water prevented, the rats were placed into the box again andpermitted access to water on condition that an electric current waspassed between the metal drinking tube and the grid to give anelectroshock for every 20 times of water drinking behavior to measurethe frequency of water drinking behavior for 3 minutes. Anxiolyticeffect was evaluated as relieving rate of anxiety as calculated by thefollowing equation.

Relieving rate of anxiety=(C-B)/(A-B)×100

A: Frequency of water drinking behavior of a control group without anelectroshock and no anxiety (frequency under no punishment)

B: Frequency of water drinking behavior of a group with an electroshockand anxiety (under punishment) and having been administered a solventcontaining no test compound (frequency under solvent-control group)

C: Frequency of water drinking behavior of a group having beenadministered a test compound and relieved anxiety (frequency under testcompound-administered group)

                  TABLE 7                                                         ______________________________________                                        Anticonflict Test                                                                              Dose    Relieving rate of                                    Test compound    (mg/kg) anxiety (%)                                          ______________________________________                                        Compound 1'a-1   0.01    93                                                                    0.1     86                                                                    1.0     76                                                   Compound 1'a-5   0.01    89                                                   Compound 1'b-1   0.01    80                                                   Compound 1'''-8  0.01    96                                                   Compound 1'''-9  0.01    96                                                   Comparison Compound                                                                            0.01    43                                                                    0.1     44                                                                    1.0     46                                                   Diazepam         1.0     -3                                                   Buspirone        1.0     2                                                    ______________________________________                                    

From the above, the present compound decreased anxiety almost nearly100% at low doses of 0.01 to 0.1 mg/kg. Contrary, the comparisoncompound decreased anxiety up to 50% at the same dose. Diazepam andbuspirone were found almost ineffective even at a dose of 1.0 mg/kg.Accordingly, the present compound exhibits extremely excellentanxiolytic effect.

Test Example 2 Muscle Relaxant Effect (Traction Method)

1. Experimental animals and administration method

Compound 1'a-1, the comparison compound, diazepam or busipirone wassuspended in a 0.5% sodium carboxymethyl cellulose solution, and thesuspension was orally administered to 3- to 4-week-old male ddY mice (ingroups of 5) in a volume of 10 ml/kg one hour before the start ofexperiment.

2. Experimental method and result

With reference to a method described in Japan J. Pharmacol., 49. 337˜349(1989), the foreleg of the mouse was hung on a horizontal wire, having adiameter of 1.2 mm and fixed at a level of 30 cm, three timesconsecutively. If the hind leg did not touch the wire within 10 secondseach time, the result was interpreted as positive. Thus, ED₅₀ wasdetermined for evaluation. Consecutively, Compound 1'a-1 and thecomparison compound exhibited no muscle relaxant effect even when givenat a dose of 300 mg/kg. Diazepam and busipirone were 2.2 mg/kg and 427.8mg/kg, respectively, in ED50.

Test Example 3 Sedative Effect (Spontaneous locomotor activity)

1. Experimental animals and administration method

Compound 1'a-1, the comparison compound, diazepam or buspirone wassuspended in a 0.5% sodium carboxymethyl cellulose solution, and thesuspension was orally administered to 3- to 4-week-old male ddY mice (ingroups of 5) in a volume of 10 ml/kg one hour before the start ofexperiment.

2. Experimental method and result

The test was conducted with reference to a method described in"Evaluation of Medicinal Efficacies (1), Pharmacological Test Method(I), Basic Lectures on Development of Pharmaceuticals," 50˜54(1971).More specifically, the group of mice were given the test drug andthereafter measured the amount of spontaneous locomotor activity for 10minutes per mouse using Animex MK-110 (Muromachi Kikai Co., Ltd.). Whenthe amount of activity was up to 50% of the control group, the resultwas interpreted as positive to determine ED₅₀ for evaluation.Consequently, Compound 1'a-1 and the comparison compound exhibited nosedative effect even at a dose of 300 mg/kg. Diazepam and buspirone were1.7 mg/kg and 149.7 mg/kg, respectively, in the above value.

Test Example 4 Effect on central nervous system depressant (Ethanolenhancing method)

1. Experimental method and administration method

Compound 1'a-1, the comparison compound, diazepam or buspirone wassuspended in a 0.5% sodium carboxymethyl cellulose solution, and thesuspension was orally administered to 3- to 4-week-old male ddY mice (ingroups of 6) in a volume of 10 ml/kg one hour before the start ofexperiment.

2. Experimental method and result

The test was conducted with reference to a method described in Japan. J.Pharmacol., 49, 337˜349(1989). More specifically, the group of mice wereintraperitoneally given 25% ethanol at a dose of 20 ml/kg and checkedfor the time interval between loss and recovery of the righting reflex.When the time measurement was in excess of twice the measurement of thecontrol group, the result was interpreted as positive to determine ED₅₀for evaluation. Consequently, Compound 1'a-1 and the comparison compoundproduced no ethanol enhancing effect even at a dose of 300 mg/kg.Diazepam and buspirone were 0.48 mg/kg and 120.1 mg/kg, respectively, inthe value.

Test Example 5

Anticonvlusant Effect (Pentylenetetrazol-induced Convulsion Method)

1. Experimental method and administration method

Compound 1'a-1, the comparison compound, diazepam or busipirone wassuspended in a 0.5% sodium carboxymethyl cellulose solution, and thesuspension was orally administered to 3- to 4-week-old male ddY mice (ingroups of 6) in a volume of 10 ml/kg one hour before the start ofexperiment.

2. Experimental method and result

The test was conducted with reference to a method described in"Evaluation of Medicinal Efficacies (1), Pharmacological Test Method(I), Basic Lectures on Development of Pharmaceuticals," 167˜172(1971).More specfically, pentylenetetrazol was subcutaneously administered tothe mouse at a dose of 150 mg/kg, and when the mouse did not die due toonset of convulsion within 60 minutes, the result was interpreted aspositive to determine Ed₅₀ for evaluation. Consequently, Compound 1'a-1and the comparison compound exhibited no anticonvulsant effect even at adose of 300 mg/kg. Diazepam and buspirone were 0.35 mg/kg and at least300 mg/kg, respectively, in the value.

Test Example 6 Acute Toxicity Test

Five-week-old male ddY mice were used in groups of, 6. The mice wereorally given the test compound as suspended in a 5.0% sodiumcarboxymethyl cellulose solution and thereafter observed for 3 days tomeasure the number of deaths at each of doses. Table 8 shows the result.

                  TABLE 8                                                         ______________________________________                                        Acute Toxicity Test                                                                       Dose       Number of                                                                              Number of                                     Test compound                                                                             (mg/kg)    animal   death                                         ______________________________________                                        Compound 1'a-1                                                                            2000       6        0                                             Compound 1'a-1                                                                            3000       6        2                                             Comprn. compnd                                                                            2000       6        1                                             Comprn. compnd                                                                            3000       6        5                                             ______________________________________                                    

From the above, although 5 mice died amount 6 mice at a dose of 3000mg/kg in the comparison compound, only two mice died among 6 in thepresent compound. Accordingly, the present compound is low in toxicityand high in safety compared with the comparison compound

INDUSTRIAL APPLICABILITY

The bicyclolactam derivative represented by the formula (1) has anexcellent anxiolytic effect, is reduced in side effects such as sedativeand muscle relaxant effects and is low in toxicity. Accordingly, theagent comprising the present compound as an effective component isuseful for treating or preventing chronic or acute anxiety disorders (oranxiety and fear neuroses), such as panic disorder accompanied or notaccompanied by agoraphobia, social phobia or simple phobia,obsessive-compulsive disorder (neurosis), stress disorder resulting frominjury and systemic anxiety disorder, and other anxiety disorders, andalso for relieving healthy persons and the aged of anxiety.

Additionally, the present invention is useful for treating or preventingthe anxiety attendant on withdrawal symptons due to drug dependanceand/or drug addicition. Thus, the present invention is useful forallaying withdrawal symptons due to alcohol dependence, nicotinedependence, cocaine dependance and benzodiazepine dependence andwithdrawal symptons due to other drug dependence.

We claim:
 1. A bicyclolactam compound represented by the followingformula (1) ##STR39## wherein R is oxo or --OR¹, wherein R¹ is selectedfrom the group consisting of a hydrogen atom, a C₂ -C₆ acyl group,benzoyl, 3-toluyl, 4-toluyl, 2- methoxybenzoyl, 2,4-dimethoxybenzoyl,α-naphthylcarbonyl and β-naphthylcarbonyl;A is a group (2) or (3)##STR40## wherein R² is a substituted or unsubstituted benzoyl group; Qis hydrogen or a straight-chained or branched C₁ -C₆ alkyl group; I is1; m is 1; and n is
 1. 2. A process for preparing a bicyclolactamcompound represented by the following formula (1') ##STR41## wherein Ais a group (2) or (3) ##STR42## wherein R² is a substituted orunsubstituted benzoyl group;Q is hydrogen or a straight-chained orbranched C₁ -C₆ alkyl group; I is 1; m is 1; and n is 1,the processcomprising: hydrogenating a compound of the formula (4) ##STR43##wherein A, Q, I, m and n are as defined above, and R³ is anunsubstituted or substituted benzyl group, in a solvent in the presenceof a catalyst, to produce the compound of formula (1').
 3. Abicyclolactam compound represented by the following formula (1)##STR44## wherein R is oxo or --OR¹, wherein R¹ is selected from thegroup consisting of a hydrogen atom, a C₂ -C₆ acyl group, benzoyl,3-toluyl, 4-toluyl, 2-methoxybenzoyl, 2,4-dimethoxybenzoyl,α-napththylcarbonyl and β-naphthylcarbonyl;A is a group (2) or (3)##STR45## wherein R² is a substituted or unsubstituted benzoyl group; Qis hydrogen or a straight-chained or branched C₁ -C₈ alkyl group; I is2; m is 0; and n is
 2. 4. A process for preparing a bicyclolactamcompound represented by the following formula (1') ##STR46## wherein Ais a group (2) or (3) ##STR47## wherein R² is a substituted orunsubstituted benzoyl group;Q is hydrogen or a straight-chained orbranched C₁ -C₆ alkyl group; I is 2; m is 0; and n is 2,the processcomprising: hydrogenating a compound of the formula (4) ##STR48##wherein A, Q, I, m, and n are as defined above, and R³ is anunsubstituted or substituted benzyl group, in a solvent in the presenceof a catalyst, to produce the compound of the formula (1').
 5. Abicyclolactam compound represented by the following formula (1)##STR49## wherein R is oxo or --OR¹, wherein R¹ is selected from thegroup consisting of a hydrogen atom, a C₂ -C₆ acyl group, benzoyl,3-toluyl, 4-toluyl, 2-methoxybenzoyl, 2,4-dimethoxybenzoyl, α-naphthylcarbonyl and β-naphthylcarbonyl;A is a group (2) or (3)##STR50## wherein R² is substituted or unsubstituted benzoyl group; Q ishydrogen or a straight-chained or branched C₁ -C₆ alkyl group; I is 2; mis 1; and n is
 1. 6. A process for preparing a bicyclolactam compoundrepresented by the following formula (1') ##STR51## wherein A is a group(2) or (3) ##STR52## wherein R² is a substituted or unsubstitutedbenzoyl group;Q is hydrogen or a straight-chained or branched C₁ -C₆alkyl group; I is 2; m is 1; and n is 1,the processing comprising:hydrogenating a compound of the formula (4) ##STR53## wherein A, Q, I,m, and n are as defined above, and R³ is an unsubstituted or substitutedbenzyl group, in a solvent in the presence of a catalyst, to produce thecompound of the formula (1').
 7. A bicyclolactam compound represented bythe following formula (4) ##STR54## wherein R³ is a substituted orunsubstituted benzyl group;A is a group (2) or (3) ##STR55## wherein R²is a substituted or unsubstituted benzoyl group; Q is hydrogen or astraight-chained or branched C₁ -C₆ alkyl group; I is 1; m is 1; and nis
 1. 8. A bicyclolactam compound represented by the following formula(4) ##STR56## wherein R³ is a substituted or unsubstituted benzylgroup;A is a group (2) or (3) ##STR57## wherein R² is a substituted orunsubstituted benzoyl group; Q is hydrogen or a straight-chained orbranched C₁ -C₆ alkyl group; I is 2; m is 0; and n is
 2. 9. Abicyclolactam compound represented by the following formula (4)##STR58## wherein R³ is a substituted or unsubstituted benzyl group;A isa group (2) or (3) ##STR59## wherein R² is a substituted orunsubstituted benzoyl group; Q is hydrogen or a straight-chained orbranched C₁ -C₈ alkyl group; I is 2; m is 1; and n is
 1. 10. Apharmaceutical composition comprising an effective amount of thebicyclolactam compound of claim 1 and a pharmaceutically acceptablecarrier.
 11. A pharmaceutical composition comprising an effective amountof the bicyclolactam compound of claim 3 and a pharmaceuticallyacceptable carrier.
 12. A pharmaceutical composition comprising aneffective amount of the bicyclolactam compound of claim 5 and apharmaceutically acceptable carrier.
 13. A method of treating anxiety ina patient, comprising administering to the patient an anxiety treatingeffective amount of the bicyclolactam compound of claim
 1. 14. A methodof treating anxiety in a patient, comprising administering to thepatient an anxiety treating effective amount of the bicyclolactamcompound claim
 3. 15. A method of treating anxiety in a patient,comprising administering to the patient an anxiety treating effectiveamount of the bicyclolactam compound claim 5.